Pyridine carboxamide compounds that inhibit nav1. 8

Abstract

Nav1. 8 blockers, methods of modulating Nav1. 8 sodium ion channels, and methods of treating and / or alleviating the symptoms of conditions, diseases or disorders associated with increased Nav1. 8 activity or expression are provided.SOLUTION: Provided are pyridine carboxamide compounds for inhibiting Nav1. 8. Specific examples thereof include N - (1, 3-benzothiazol-6-yl) - 2 - (4-fluoro-2-methoxy-phenoxy) - 5 - (trifluoromethyl) pyridine-3-carboxamide. Also provided is a method of modulating a Nav1. 8 sodium ion channel, comprising administering to a subject in need thereof a modulating effective amount of the compound to the subject.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application is a continuation of U.S. Provisional Application No. 62 / 695,571, filed July 9, 2018. The benefit of this application is claimed and is incorporated herein by reference in its entirety. [Background technology]

[0002] Modern pharmacopoeias include steroidal and nonsteroidal anti-inflammatory drugs (NSAIDs), amines, and There are various treatments for acute and chronic pain, including reuptake inhibitors and opioids (analgesics). There are treatments available. All have drawbacks, especially in the current opioid abuse epidemic (Skolnic In light of the recent trend toward pain management (K, 2018), extensive efforts have been made to develop novel approaches to pain management. The voltage-dependent natto Sodium channels (Na v ) (Catterall 2012) is a neurotransmitter for sensory neurons. Given its important role in conduction, it is a reasonable target for pain management. (Ruiz et al., 2015).

[0003] There are a total of nine known subtypes of the major pore-forming α subunits. v 1.1, Na v 1.2 and Na v The 1.3 subtype is primarily expressed in the central nervous system (CNS) and v 1.4 and Na v 1.5 is abundant in skeletal and cardiac muscles. v 1.6 Peripheral nerves It has been shown to be expressed in both the pulmonary nucleus (PNS) and central nervous system (CNS), but Na v 1.7, N a v 1.8 and Nav 1.9 is usually considered to be restricted to the PNS (Yu and Catterall, 2003). Nonselective sodium channel inhibitors are It is available as an antiarrhythmic, anticonvulsant and local anesthetic, but is also a common treatment for chronic pain. (Eijkelkamp, ​​et al., 2012). Na v The family is highly homologous, and obtaining selective drug-like ligands is an important challenge. However, certain isoforms Selective inhibitors (Jukic, et al., 2014) or activators (Deuis , et al., 2017) holds promise for many disorders.

[0004] Na v 1.7 and Na v Both isoforms 1 and 8 are present in nociceptors of the PNS. Therefore, it has attracted much attention as a target for pain treatment (Jukic, et al. 2014). Extensive human genetic validation of this channel (Bennett and Wo ods, 2014) and the discovery of a class of selective inhibitors (McCormack et al. l., 2013), Na v Active efforts are underway towards 1.7 (V However, some selective Na v 1.7 hindrance Human clinical trials of anti-inflammatory drugs have been disappointing (Donnell et al., 201 8; Zakrzewska et al., 2017), Na v 1.8 is the alternate target It has been suggested that this is the case (Han et al., 2016).

[0005] Na v 1.8 The pore-forming α subunit of the sodium channel is encoded by the SCN10A gene. and is encoded by α-glucan, primarily in dorsal root ganglion (DRG) neurons and in the trigeminal and nodose ganglia It is expressed in (but not limited to) neurons (Akopian et al. al., 1996; Shields et al., 2012). The ion is the depolarization phase of the neural action potential, which is important for the propagation and repetitive firing of the action potential, and occurs in most Mediates inward sodium currents (Akopian et al., 1999). Knockout and knockdown studies of the SCN10A gene in rodents have shown that it inhibits inflammatory and neuropathic Na for sexual pain v 1.8 has been shown to be involved (Dong et al., Heterozygous gain-of-function mutations in SCN10A cause abnormal development of DRG neurons. This has been linked to painful small fiber neuropathy in humans. Na v This further strengthens the link between 1.8 and the function of nociceptive neurons (Faber et al., 2012 ).

[0006] Na v 1.8 inhibitors have potential beyond pain treatment. v 1.8 is expressed in the brain (Lu et al., 2015) and is involved in the pathogenesis of multiple sclerosis (MS). There is growing evidence that Na v 1.8 is an experimental Autoimmune encephalomyelitis (EAE) mice (Black et al., 2000) and MS in the cerebellar Purkinje neurons of patients ( Damarjian et al., 2004 ). It has been shown to be ectopically expressed. v Ectopic expression of 1.8 inhibits cerebellar proliferation. Abnormal firing patterns in Lukinje cells occur, and the mouse model shows no obvious signs of ataxia. Despite this, impaired motor coordination occurs (Shields et al., 201 2).

[0007] Importantly, Na v 1,8-blocker N-methyl-6-amino-5-(2,3,5-trimethyl-2- ... Treatment with (trichlorophenyl)pyridine-2-carboxamide (PF01247324) reverses cerebellar damage in a mouse model of MS, thereby potentially treating MS. This paper establishes a potential novel approach for 15) Cortical neurons in an ex vivo cortical development model in which transcription factor 4 (TCF4) was disrupted Data on the physiological function of TCF4 suggest that TCF4 normally regulates the SCN10A gene in the CNS. We demonstrate in vivo evidence that TCF4 haploinsufficiency suppresses expression. A genetic form of autism called Pitt-Hopkins syndrome (PTHS), defined as in vivo cell models and two independent rodent models (Sweatt, 2 013), TCF4 deficiency results in abnormal electrophysiological changes characterized by a marked reduction in action potential output. These phenotypes were observed in SCN10A(Na v 1.8) is associated with increased expression It has been shown that these P In the THS model, N-[6-amino-5-(2-chloro-5-methoxyphenyl)pyridinyl] [Zin-2-yl]-1-methyl-1H-pyrazole-5-carboxamide (PF 453 1083) and 5-4(-chlorophenyl)-N-(3,5-dimethoxyphenyl)furafine Na-2-carboxamide (A-803467) v 1.8 Inhibitors, excitatory expression These results show that the morphology can be rapidly restored. Peripherally restricted sodium channel Na v Ectopic expression of 1.8 in the brain is associated with PTH It may be causing some of the symptoms of S, and Na v 1.8 inhibitors in PTHS patients This suggests that it may have therapeutic value for

[0008] Na v The 1.8 channel is a structure related to the back (Bucknill et al., 2 002) and dental pulp (Renton et al., 2005), pain (Shembalkar et al., 2001) and inflammatory bowel disease (Beyak and Vanner, 2005) also found that Na v 1.8 channels involved There is evidence that this is the case.

[0009] Na v 1.8 is similar to most other members of the family of voltage-gated ion channels. has a major difference that inhibits most other members of the family. It is "resistant" to inhibition by tetrodotoxin, a potent sodium channel blocker. (Cestele and Catterall, 2000). v 1.8 Inhibitors, such as N-methyl-6-amino-5-(2,3,5-trichlorophenoxy) (I)pyridine-2-carboxamide (PF 01247324) (Bagal et al. l., 2015), 5-4(-chlorophenyl)-N-(3,5-dimethoxyphenyl ) furan-2-carboxamide (A-803467) (Kort et al., 20 08) and 5-(4-butoxy-3-chlorophenyl)-N-[[2-(4-morpholinyl) (Z)-3-pyridinyl]methyl-3-pyridinecarboxamide (A-887826) Hang et al., 2010) are known in the literature (Figure 1 (Prior Art) Its efficacy in various pain models has been investigated, including inflammatory pain, neuropathic pain, and effect was seen in both rodent models ( Jarvis et al., 2007 ; Payne et al., 2015). These compounds and others similar to them has various drawbacks, such as selectivity over other ion channels and poor pharmacokinetics. Summary of the Invention

[0010] In some embodiments, the subject matter of the present disclosure is a compound of formula (I): [ka] [In the formula, X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R1 is aryl or heteroaryl, and the aryl or heteroaryl is unsubstituted or mono-, di- and trihalo-C1-C4 alkyl, substituted or is unsubstituted C1-C8 alkyl, C3-C 10 Cycloalkyl, halogen, heteroaryl , cyano, amino, nitro, aryloxyl, aryl, C1-C8 alkoxyl, molybdenum No-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfa substituted with one or more groups selected from the group consisting of aryl and arylalkoxyl; It has been; R2 is selected from the group consisting of aryl, heteroaryl, and heterocycle; Heteroaryls and heterocycles are unsubstituted or include mono-, di- and trihalo-C1- C4 alkyl, substituted or unsubstituted C1-C8 alkyl, C3-C 10 cycloalkyl, Halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C 1-C8 alkoxyl, mono-, di- or trihaloalkoxyl, arylalkoxy Sil, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfano alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl substituted with one or more groups selected from the group R3 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, when Y is carbon. Di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alk xyl, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, -NO2, - N + (=O)-O - and is absent when Y is nitrogen; R4 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo -C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted and unsubstituted C1-C8 alkyl and morpholinyl, provided that R3 and and R4 are not simultaneously hydrogen; or R3 and R4 together represent a C3-C5 carbon atom, including the carbon atom to which R3 and R4 are attached. forming a carbocyclic ring]; and pharmaceutically acceptable salts thereof.

[0011] In certain embodiments of compounds of formula (I): X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R1 is selected from the group consisting of phenyl or pyridinyl, Lysinyl is unsubstituted or can be substituted or unsubstituted C1-C8 alkyl, halogen, -O-R5 (wherein R5 is C1-C8 alkyl, -CF3, -CHF2 and -(CH2 ) p -CF3, where p is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8 and -S-CF3, wherein each R is an integer selected from the group consisting of substituted with one or more groups selected from the group consisting of: R2 is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1 -oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzoxazole phenyl, pyridyl, pyrimidinyl, pyridyl, thiazolyl; Dinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl C1- and 1,3-benzothiazolyl are unsubstituted or unsubstituted or substituted C1- C8 alkyl, halogen, cyano, oxo, -O-R5 (wherein R5 is C1-C8 alkyl) -(CH), -(CH) q -OH(expression wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; -NR6R7, where R6 and R7 are selected from the group consisting of H and C1-C4 alkyl; morpholinyl, oxazolyl, -C(=O)-R8 (wherein R8 is -NR6R 7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 alkyl; and C1-C4 alkyl), -S(=O)-R9, -S(=O)2 -R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2( wherein each R is independently C-C alkyl, -CF, or -NR, R, R6 and R7 are selected from the group consisting of H and C1-C4 alkyl, and R 10 teeth H or C1-C4 alkyl, and R 11 is C1-C4 alkyl) and substituted with one or more groups selected from the group consisting of: Y is nitrogen and R2 is phenyl or With the proviso that in the case of pyridyl, R8 cannot be -NR6R7; R3 is hydrogen, cyano, halogen, -CF3, C1-C8 alkoxy when Y is carbon. xyl, -O-CH(F)2, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkenyl selected from the group consisting of alkyl, NO2, and absent when Y is nitrogen; R4 is hydrogen, cyano, halogen, C1-C8 alkoxyl, -CF3, substituted or unsubstituted C1-C8 alkyl, and morpholinyl, provided that R3 and R4 are the same. provided that it is not hydrogen; or R3 and R4 together represent a C3-C5 carbon atom, including the carbon atom to which R3 and R4 are attached. Forms a carbocyclic ring; and pharmaceutically acceptable salts thereof.

[0012] In a further particular embodiment of the compound of formula (I), the compound has the structure: [ka] [In the formula, X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R2 is selected from the group consisting of aryl, heteroaryl, and heterocycle; Heteroaryls and heterocycles are unsubstituted or include mono-, di- and trihalo-C1- C4 alkyl, substituted or unsubstituted C1-C8 alkyl, C3-C 10 cycloalkyl, Halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C 1-C8 alkoxyl, mono-, di- or trihaloalkoxyl, arylalkoxy Sil, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfano alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl substituted with one or more groups selected from the group R3 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, when Y is carbon. Di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alk xyl, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, -NO2 and absent when Y is nitrogen; R4 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo -C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted and unsubstituted C1-C8 alkyl and morpholinyl, provided that R3 and and R4 are not simultaneously hydrogen; or R3 and R4 together represent a C3-C5 carbon atom, including the carbon atom to which R3 and R4 are attached. forming a carbocyclic ring; n is an integer selected from 0, 1, 2, 3, 4 and 5; Each R 24 are independently mono-, di- and trihalo-C1-C4 alkyl, substituted or unsubstituted Substituted C1-C8 alkyl, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano No, amino, nitro, aryloxyl, aryl, C1-C8 alkoxyl, mono-, Di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and selected from the group consisting of arylalkoxyl]; and pharmaceutically acceptable salts thereof.

[0013] In certain embodiments of compounds of Formula (I'), R2 is selected from the group consisting of: [ka] [In the formula, m is an integer selected from the group consisting of 0, 1, 2, 3 and 4; R 25 is H, morpholinyl, oxazolyl, halogen, cyano, -(CH2) q -OH wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. , -C(=O)-R8 (wherein R8 is the group consisting of -NR6R7 and C1-C4 alkyl) and R6 and R7 are selected from the group consisting of H and C1-C4 alkyl. , -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 average and -N=S(=O)-(R 11 )2 (wherein each R9 is independently C1-C4 alkyl , -CF3 or -NR6R7 (wherein R6 and R7 are selected from the group consisting of H and C1-C4 alkyl). is selected from the group 10 is H or C1-C4 alkyl, and R 11 is C1 -C4 alkyl), wherein Y is nitrogen and R2 is phenyl or With the proviso that in the case of pyridyl, R8 cannot be -NR6R7; R 26 is halogen or cyano; Each R 27 are independently H, halogen, C1-C8 alkoxyl, cyano, and -NR6R 7 selected from the group consisting of; Each R 28 are independently H or C1-C4 alkyl.

[0014] In another aspect, the presently disclosed subject matter provides Na v 1.8 Sodium ion channel regulators A method for treating a subject in need thereof, comprising administering to said subject a compound of formula (I) in an amount effective to modulate said subject. The method includes administering a compound of formula (I) to a subject.

[0015] In another aspect, the presently disclosed subject matter provides Na v 1.8, but without the need for it. administering to a subject suffering from the condition an inhibitory effective amount of a compound of formula (I) to said subject. A method is provided.

[0016] In yet another aspect, the presently disclosed subject matter provides a method for treating Na v Associated with increased activity or expression of 1.8 A method of treating a condition, disease or disorder comprising administering to a subject in need thereof a The present invention provides a method comprising administering to the body a therapeutically effective amount of a compound of formula (I).

[0017] In certain embodiments, Na v1.8 Pathological conditions, diseases or disorders associated with increased activity or expression , pain, respiratory disorders, neurological disorders and psychiatric disorders, and combinations thereof. It is selected.

[0018] Certain aspects of the presently disclosed subject matter described above may be incorporated in whole or in part by the presently disclosed subject matter. While other aspects are described in the accompanying embodiments best described herein below, This will become clearer as the description proceeds with reference to examples. [Brief explanation of the drawings]

[0019] Having thus described the subject matter of the present disclosure in general terms, reference is now made to the accompanying drawings, in which: However, these are not necessarily drawn to scale. [Figure 1] FIG. 1 depicts representative preclinical and clinical NaV1.8 inhibitors known in the art (prior art). DETAILED DESCRIPTION OF THE INVENTION

[0020] The subject matter of the present disclosure is described in further detail below. The subject matter of the present disclosure can be used in many different The present invention should not be construed as being limited to the embodiments set forth herein. rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. Indeed, many modifications and other embodiments of the disclosed subject matter described herein may be accomplished in accordance with the foregoing description. It will occur to one skilled in the art to which the subject matter of this disclosure pertains having the benefit of the teachings presented herein. Therefore, it is to be understood that the subject matter of this disclosure is not limited to the particular embodiments disclosed. However, modifications and other embodiments are intended to be within the scope of the appended claims. Please understand that.

[0021] (Na V 1. Pyridine carboxamide compounds for inhibiting 8) The subject matter of the present disclosure is sodium channel inhibitors and Na v Increased activity or expression of 1.8 Their use for treating associated conditions, diseases or disorders is provided.

[0022] In some embodiments, the subject matter of the present disclosure is a compound of formula (I): [ka] [In the formula, X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R1 is aryl or heteroaryl, and the aryl or heteroaryl is unsubstituted or mono-, di- and trihalo-C1-C4 alkyl, substituted or is unsubstituted C1-C8 alkyl, C3-C 10 Cycloalkyl, halogen, heteroaryl , cyano, amino, nitro, aryloxyl, aryl, C1-C8 alkoxyl, molybdenum No-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfa substituted with one or more groups selected from the group consisting of aryl and arylalkoxyl; It has been; R2 is selected from the group consisting of aryl, heteroaryl, and heterocycle; Heteroaryls and heterocycles are unsubstituted or include mono-, di- and trihalo-C1- C4 alkyl, substituted or unsubstituted C1-C8 alkyl, C3-C 10 cycloalkyl, Halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C 1-C8 alkoxyl, mono-, di- or trihaloalkoxyl, arylalkoxy Sil, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfano alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl substituted with one or more groups selected from the group R3 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, when Y is carbon. Di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alk xyl, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, -NO2 and absent when Y is nitrogen; R4 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo -C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted and unsubstituted C1-C8 alkyl and morpholinyl, provided that R3 and and R4 are not simultaneously hydrogen; or R3 and R4 together represent a C3-C5 carbon atom, including the carbon atom to which R3 and R4 are attached. forming a carbocyclic ring]; and pharmaceutically acceptable salts thereof.

[0023] In some embodiments of the compounds of Formula (I): X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R1 is phenyl or pyridinyl, and said phenyl or pyridinyl is a non-substituted or substituted or unsubstituted C1-C8 alkyl, halogen, -O-R5 (wherein , R5 is C1-C8 alkyl, -CF3, -CHF2 and -(CH2) p -CF3(formula wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. and one or more selected from the group consisting of -S-CF3 substituted with a number of groups; R2 is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1 -oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzoxazole phenyl, pyridyl, pyrimidinyl, pyridyl, thiazolyl; Dinyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl C1- and 1,3-benzothiazolyl are unsubstituted or unsubstituted or substituted C1- C8 alkyl, halogen, cyano, oxo, -O-R5 (wherein R5 is C1-C8 alkyl) -(CH), -(CH) q -OH(expression wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; -NR6R7, where R6 and R7 are selected from the group consisting of H and C1-C4 alkyl; morpholinyl, oxazolyl, -C(=O)-R8 (wherein R8 is -NR6R 7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 alkyl; and C1-C4 alkyl), -S(=O)-R9, -S(=O)2 -R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2( wherein each R is independently C-C alkyl, -CF, or -NR, R, R6 and R7 are selected from the group consisting of H and C1-C4 alkyl, and R 10 teeth H or C1-C4 alkyl, and R 11 is C1-C4 alkyl) and substituted with one or more groups selected from the group consisting of: Y is nitrogen and R2 is phenyl or With the proviso that in the case of pyridyl, R8 cannot be -NR6R7; R3 is hydrogen, cyano, halogen, -CF3, C1-C8 alkoxy when Y is carbon. xyl, -O-CH(F)2, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkenyl -alkyl, -NO2, and absent when Y is nitrogen; R4 is hydrogen, cyano, halogen, C1-C8 alkoxyl, -CF3, substituted or unsubstituted C1-C8 alkyl, and morpholinyl, provided that R3 and R4 are the same. provided that it is not hydrogen; or R3 and R4 together represent a C3-C5 carbon atom, including the carbon atom to which R3 and R4 are attached. Forms a carbocyclic ring; and pharmaceutically acceptable salts thereof.

[0024] In certain embodiments of the compounds of Formula (I), the compounds have the following structure: [ka] [In the formula, X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R2 is selected from the group consisting of aryl, heteroaryl, and heterocycle; Heteroaryls and heterocycles are unsubstituted or include mono-, di- and trihalo-C1- C4 alkyl, substituted or unsubstituted C1-C8 alkyl, C3-C 10 cycloalkyl, Halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C 1-C8 alkoxyl, mono-, di- or trihaloalkoxyl, arylalkoxy Sil, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfano alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl substituted with one or more groups selected from the group R3 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, when Y is carbon. Di- and trihalo-C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alk xyl, substituted or unsubstituted C1-C8 alkyl, C3-C8 cycloalkyl, -NO2 and absent when Y is nitrogen; R4 is hydrogen, cyano, halogen, C1-C8 alkoxyl, mono-, di- and trihalo -C1-C4 alkyl, mono-, di- and trihalo-C1-C4 alkoxyl, substituted or unsubstituted and unsubstituted C1-C8 alkyl and morpholinyl, provided that R3 and and R4 are not simultaneously hydrogen; or R3 and R4 together represent a C3-C5 carbon atom, including the carbon atom to which R3 and R4 are attached. forming a carbocyclic ring; n is an integer selected from 0, 1, 2, 3, 4 and 5; Each R 24 are independently mono-, di- and trihalo-C1-C4 alkyl, substituted or unsubstituted Substituted C1-C8 alkyl, C3-C 10 Cycloalkyl, halogen, heteroaryl, cyano No, amino, nitro, aryloxyl, aryl, C1-C8 alkoxyl, mono-, Di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and selected from the group consisting of arylalkoxyl]; and pharmaceutically acceptable salts thereof.

[0025] In certain embodiments of compounds of Formula (I'), R2 is selected from the group consisting of: [ka] [In the formula, m is an integer selected from the group consisting of 0, 1, 2, 3 and 4; R 25 is H, morpholinyl, oxazolyl, halogen, cyano, -(CH2) q -OH wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. , -C(=O)-R8 (wherein R8 is the group consisting of -NR6R7 and C1-C4 alkyl) and R6 and R7 are selected from the group consisting of H and C1-C4 alkyl. , -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 average and -N=S(=O)-(R 11 )2 (wherein each R9 is independently C1-C4 alkyl , -CF3 or -NR6R7 (wherein R6 and R7 are selected from the group consisting of H and C1-C4 alkyl). is selected from the group 10 is H or C1-C4 alkyl, and R 11 is C1 -C4 alkyl), wherein Y is nitrogen and R2 is phenyl or With the proviso that in the case of pyridyl, R8 cannot be -NR6R7; R 26 is halogen or cyano; Each R 27 are independently H, halogen, C1-C8 alkoxyl, cyano, and -NR6R 7 selected from the group consisting of; Each R 28 are independently H or C1-C4 alkyl.

[0026] In some embodiments, the compound of Formula (I) is a compound of Formula (IF): [ka] [In the formula, R2 is selected from the group consisting of aryl and heteroaryl, Aryl is optionally substituted with cyano, heterocycloalkyl, -S(=O)-R9, -S( =O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R1 1)2 (wherein each R9 is independently C1-C4 alkyl, -CF3, or -NR6R7) wherein R6 and R7 are selected from the group consisting of H and C1-C4 alkyl; R 10 is H or C1-C4 alkyl, and R 11 is C1-C4 alkyl) substituted with a substituent selected from the group consisting of: R 12 is a halogen; R 13 is C1-C4 alkyl].

[0027] In some embodiments of the compound of Formula (IF), the aryl and heteroaryl are , phenyl, benzothiazolyl, pyridyl, pyridyl N-oxide and pyrimidinyl each of which is optionally selected from the group consisting of cyano, heterocycloalkyl, -S( =O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N =S(=O)-(R 11 )2 (wherein each R9 is independently C1-C4 alkyl, -CF 3 or -NR6R7, where R 10is H or C1-C4 alkyl, and R 11 is C1- C4 alkyl); R 12 is fluorine; R 13 is methyl.

[0028] In certain embodiments of compounds of Formula (IF), R2 is 1,3-benzothiazole-6 -yl, 3-morpholinophenyl, 3-cyanophenyl, 4-cyanophenyl, 3-pyri 4-pyridyl, 6-cyano-3-pyridyl, 3-methylsulfinylphenyl, 3 -oxazol-5-ylphenyl, 3-dimethylsulfamoylphenyl, 1,3-benzylphenyl benzothiazol-2-yl, pyrimidin-4-yl, (trifluorosulfonyl)phenyl 3-(methylsulfonimidoyl)phenyl, 2-methoxy-4-pyridyl, 3-( N,S-dimethylsulfonimidoyl)phenyl, 2-methyl-4-pyridyl, 6-methyl dimethyl-3-pyridyl, pyridazin-4-yl and dimethyl(oxo)-λ 6 -Sulfanili [phenyl]amino]phenyl.

[0029] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IG): [ka] [In the formula, R1 is one or more of C1-C8 alkyl, halogen, and C1-C8 alkoxyl. and wherein the C1-C8 alkoxyl is optionally one or is substituted with multiple halogens; R 14 is C1-C4 alkyl].

[0030] In some embodiments of the compound of Formula (IG), R1 is 2,4-dichlorophenoxy phenyl, 2,4-dimethylphenyl, 2-chloro-4-methoxyphenyl, 2-propylphenyl phenyl, 2-methoxy-4-methylphenyl, 2-methoxy-4-chlorophenyl, 2- Isopropoxyphenyl, 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2-chloro- 4-fluorophenyl.

[0031] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IHi): R: [ka] [In the formula, R1 is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4-yl wherein the phenyl and pyridyl may be unsubstituted or substituted with halogen, C1-C8 alkyl, alkyl, -O-R5 (wherein R5 is C1-C8 alkyl, -CF3, -CHF2 and -( CH2) p -CF3 (wherein p is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8) -S-CF3, -NR6R7 (wherein each R is an integer selected from the group consisting of , R6 and R7 are selected from the group consisting of H and C1-C4 alkyl). May be replaced by a number; R3 and R4 are H or -CF3, but when R3 is H, R4 is -CF3, and R provided that when 4 is H, R3 is -CF3; R 14 is C1-C4 alkyl; R 15 is O or NR10 (In the formula, R 10 is H or C1-C4 alkyl) ].

[0032] In some embodiments of the compound of Formula (IHi), R1 is selected from the group consisting of phenyl, 4-fluoro 4-fluoro-2-methoxyphenyl, 2-chloro-4-fluorophenyl , 2-methyl-4-trifluoromethoxyphenyl, 4-trifluoromethoxyphenyl , difluoromethoxyphenyl, 3-fluoro-4-trifluoromethoxyphenyl, 3 -fluorophenyl, 2,5-difluorophenyl, 4-methylphenyl, 3-chloro- 5-Fluorophenyl, 2-Isopropylphenyl, 3,4-Difluorophenyl, 2,4 -difluorophenyl, 3,5-difluorophenyl, 4-(2,2,2-trifluorophenyl) Ethoxy)phenyl, 4-(trifluoromethylsulfanyl)phenyl, 2-dimethyl Aminophenyl, 2-trifluoromethylphenyl, 2,4-dimethoxyphenyl, 3,4 ,5-trifluorophenyl, 3,5-dichlorophenyl, 6-trifluoromethyl-3 -pyridyl, 1,3-benzothiazol-4-yl, 4-difluoromethoxyphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4-methoxyphenyl and 2-chloro phenyl.

[0033] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IH-ii): be,: [ka] [In the formula, R1 is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4-yl wherein the phenyl or pyridyl may be unsubstituted or substituted with halogen, C1-C8 alkyl, alkyl, -O-R5 (wherein R5 is C1-C8 alkyl, -CF3, -CHF2 and -( CH2) p -CF3 (wherein p is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8) -S-CF3, -NR6R7 (wherein each R is an integer selected from the group consisting of , R6 and R7 are selected from the group consisting of H and C1-C4 alkyl). May be replaced by a number; R3 and R4 are H or -CF3, but when R3 is H, R4 is -CF3, and R provided that if 4 is H, then R3 is -CF3.

[0034] In some embodiments of the compound of Formula (IH-ii), R1 is 2,4-dichlorofluoromethyl. phenyl, 4-difluoromethoxyphenyl and 2-chloro-4-methoxyphenyl The compound is selected from the group consisting of:

[0035] In some embodiments of the compound of Formula (I0), the compound is a compound of Formula (II) : [ka] [In the formula, R2 is selected from the group consisting of phenyl, pyridazinyl, and pyridyl, , halogen, -S(=O)-R9, -S(=O)2-R9 and -S(=O)(=NR 10 )-R 11 wherein each R is independently C-C alkyl, —CF, or —NR 7, wherein R6 and R7 are selected from the group consisting of H and C1-C4 alkyl. R 10 is H or C1-C4 alkyl, and R 11is C1-C4 alkyl) may be substituted with one or more; R 16 is a halogen; R 17 is C1-C4 alkyl].

[0036] In some embodiments of the compound of Formula (II), R2 is 3-methylsulfinyl fluoride. phenyl, 2-fluoro-5-methylsulfonylphenyl, 3-(N,S-dimethylsulfonyl)phenyl and is selected from the group consisting of (imidoyl)phenyl, pyridazinyl, and pyridyl.

[0037] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IJ): [ka] [In the formula, R2 is selected from the group consisting of phenyl and pyridyl, wherein said phenyl is selected from the group consisting of halogen, - C(=O)-R8 (wherein R8 is C1-C4 alkyl), -S(=O)-R9, - S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-( R 11 )2 (wherein each R9 is independently C1-C4 alkyl, -CF3, or -NR6R 7 and R 10 is H or C1-C4 alkyl, and R 11 is C1-C4 alkyl substituted with one or more of the following: R 18 is a halogen].

[0038] In some embodiments of compounds of Formula (IJ), R2 is 3-methylsulfonylphenyl 3-(dimethylsulfamoyl)phenyl, 3-methylsulfinylphenyl, 3-(dimethylsulfamoyl)phenyl, 2 -Fluoro-5-methylsulfonylphenyl, 3-(methylsulfonimidoyl)phenyl phenyl, 3-carbamoylphenyl, 3(N,S-dimethylsulfonimidoyl)phenyl, It is selected from the group consisting of 3-pyridyl and 4-pyridyl.

[0039] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IK): [ka] [In the formula, R1 is halogen, C1-C8 alkyl, -O-R5 (wherein R5 is C1-C8 alkyl) -CF3, -CHF2 and -(CH2) p -CF3 (wherein p is 1, 2, 3, 4, 5, 6, 7, and 8) and one or more substituted phenyl.

[0040] In some embodiments of the compound of Formula (IK), R1 is 4-fluoro-2-methoxy. Diphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4 -trifluoromethoxyphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl and 3,4-difluorophenyl.

[0041] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IL): [ka] [In the formula, R2 is selected from the group consisting of phenyl, pyridyl and pyridazin-4-yl; Phenyl is -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S (=O)-(R 11 )2 (wherein each R9 is independently C1-C4 alkyl or -NR6 R7 (wherein R6 and R7 are each H, and R 10 is H or C1-C4 alkyl R 11 is C1-C4 alkyl). In certain embodiments, R 2 is 3-(N,S-dimethylsulfonimidoyl)phenyl.

[0042] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IMi): R: [ka] [In the formula, R2 is 3-(N,S-dimethylsulfonimidoyl)phenyl or pyridin-4-yl It is; R 16 is a halogen; R 19 is C1-C4 alkyl].

[0043] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IM-ii): be: [ka] [Wherein R1 is 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl , 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2 , 4-difluorophenyl].

[0044] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IM-iii) Is: [ka] [In the formula, R1 is 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-di fluorophenyl; R 20 is C1-C4 alkyl; R 21 is H or C1-C4 alkyl].

[0045] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IM-iv): be: [ka] [Wherein R1 is 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl , 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2 , 4-difluorophenyl].

[0046] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IN): [ka] [In the formula, R2 is 3-(N,S-dimethylsulfonimidoyl)phenyl, 3-(methylsulfon selected from the group consisting of (imidoyl)phenyl and pyridazin-4-yl; R 16 is a halogen; R 19 is C1-C4 alkyl].

[0047] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IO): [ka] wherein R2 is selected from the group consisting of phenyl, pyridyl, and pyridazin-4-yl; , the phenyl is -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 and -N=S(=O)-(R 11 )2 (wherein each R9 is independently C1-C4 alkyl or -NR6R7 (wherein R6 and R7 are each H, and R 10 is H or C1-C4 alkane Kill and R 11 is C1-C4 alkyl).

[0048] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IP): [ka] [Wherein R1 is 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimeth 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2- chloro-4-fluorophenyl].

[0049] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IQ): [ka] [In the formula, R2 is phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiadiazolyl selected from the group consisting of pyrazolyl, 1,2,4-triazolyl, Phenyl is unsubstituted or substituted C1-C8 alkyl, halogen, cyano, oxo, -O -R5 (wherein R5 is selected from the group consisting of C1-C8 alkyl, -CF3 and -CHF2) (selected), -(CH2) q-OH (wherein q is 1, 2, 3, 4, 5, 6, 7, and 8) -NR6R7 (wherein R6 and R7 are integers selected from the group consisting of H and C 1-C4 alkyl), morpholinyl, oxazolyl, -C(= O)-R8 (wherein R8 is -NR6R7 (wherein R6 and R7 are H and C1-C4 alkyl groups) and C1-C4 alkyl , -S(=O)-R9, -S(=O)2-R9, -S(=O)(=NR 10 )-R 11 average and -N=S(=O)-(R 11 )2 (wherein each R9 is independently C1-C4 alkyl , -CF3 or -NR6R7 (wherein R6 and R7 are selected from the group consisting of H and C1-C4 alkyl). is selected from the group 10 is H or C1-C4 alkyl, and R 11 is C1 -C4 alkyl) the law of nature; Pyridyl is unsubstituted or substituted with C1-C8 alkyl, oxo, C1-C8 alkoxy. substituted with alkyl and halogen; R 18 is a halogen].

[0050] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IR): [ka] [In the formula, R2 is 3-(methylsulfonimidoyl)phenyl or pyridazin-4-yl; R 22 and R 23 are each C1-C4 alkyl].

[0051] In some embodiments of the compound of Formula (I), the compound is a compound of Formula (IS): [ka] [In the formula, R2 is 3-(methylsulfonimidoyl)phenyl or pyridazin-4-yl; R 16 and R 18 are halogens].

[0052] In some embodiments of the compound of Formula (I), the compound of Formula (I) is 6-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (Intermediate 3); N-(1,3-benzothiazol-6-yl)-2-(4-fluoro-2-methoxy- (phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (1); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)- 5-(trifluoromethyl)pyridine-3-carboxamide (2); N-(3-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5- (Trifluoromethyl)pyridine-3-carboxamide (3); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trimethylsilyl) Fluoromethyl)pyridine-3-carboxamide (4); N-(4-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5- (Trifluoromethyl)pyridine-3-carboxamide (5); 2-(4-fluoro-2-methoxy-phenoxy)-N-(4-pyridyl)-5-(trimethylsilyl) Fluoromethyl)pyridine-3-carboxamide (6); N-(6-cyano-3-pyridyl)-2-(4-fluoro-2-methoxy-phenoxy) -5-(trifluoromethyl)pyridine-3-carboxamide (7); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenoxy) Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide (8); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-oxazol-5-yl) Phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (9); N-[3-(dimethylsulfamoyl)phenyl]-2-(4-fluoro-2-methoxyphenyl)- -phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (10); N-(1,3-benzothiazol-2-yl)-2-(4-fluoro-2-methoxy- (phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (11); 2-(4-fluoro-2-methoxy-phenoxy)-N-pyrimidin-4-yl-5-( (trifluoromethyl)pyridine-3-carboxamide (12); 2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)-N- [3-(trifluoromethylsulfonyl)phenyl]pyridine-3-carboxamide (1 3); 2-(4-fluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimide) [(1-( ... ; 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-methoxy-4-pyridyl) )-5-(trifluoromethyl)pyridine-3-carboxamide (15); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro- 2-Methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamine Do(16); 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-methyl-4-pyridyl) -5-(trifluoromethyl)pyridine-3-carboxamide (17); 2-(4-fluoro-2-methoxy-phenoxy)-N-(6-methyl-3-pyridyl) -5-(trifluoromethyl)pyridine-3-carboxamide (18); 2-(4-fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-5-( (trifluoromethyl)pyridine-3-carboxamide (19); N-[3-[[dimethyl(oxo)]-λ 6 -sulfanylidene]amino]phenyl]- 2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridin ion-3-carboxamide (20); 2-(2,4-dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (21); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)- 5-(trifluoromethyl)pyridine-3-carboxamide (22); 2-(2-chloro-4-methoxy-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (23); N-(3-methylsulfonylphenyl)-2-(2-propylphenoxy)-5-(trimethylsulfonylphenyl)- Fluoromethyl)pyridine-3-carboxamide (24); 2-(2-Methoxy-4-methyl-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (25); 2-(4-chloro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (26); 2-(2-isopropoxyphenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (27); 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-( (trifluoromethyl)nicotinamide (28); 2-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl) (oromethyl)nicotinamide (29); 2-(2-chloro-4-methoxyphenoxy)-N-(pyridin-3-yl)-5-(trimethylsilyl) (trifluoromethyl)nicotinamide (30); 2-(3,4-difluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl) (oromethyl)nicotinamide (31); 2-(2-chloro-4-fluorophenoxy)-N-(pyridin-3-yl)-5-(trimethylsilyl) (trifluoromethyl)nicotinamide (32); 2-(2,6-dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (33); 2-(4-fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trimethylphenyl)- fluoromethyl)pyridine-3-carboxamide (34); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (I)-5-(trifluoromethyl)pyridine-3-carboxamide (35); 2-(2-chloro-4-fluoro-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (36); N-(3-methylsulfonylphenyl)-2-[2-methyl-4-(trifluorometh- yl [(c)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (37) ; N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy] si]-5-(trifluoromethyl)pyridine-3-carboxamide (38); 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (39); 2-[3-fluoro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (40)-5-(trifluoromethyl)pyridine-3-carboxamide ); N-(3-methylsulfonylphenyl)-2-phenoxy-5-(trifluoromethyl) Pyridine-3-carboxamide (41); 2-(3-fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trimethylphenyl)- fluoromethyl)pyridine-3-carboxamide (42); 2-(2,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (43); 2-(4-methylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl) (fluoromethyl)pyridine-3-carboxamide (44); 2-(3-chloro-5-fluoro-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (45); 2-(2-isopropylphenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (46); 2-(3,4-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (47); 2-(2,4-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (48); 2-(3,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (49); N-(3-methylsulfonylphenyl)-2-[4-(2,2,2-trifluoroethoxy)- [(c)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (50) ; N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]- (trifluoromethylsulfanyl)phenoxy]pyridine-3-carboxamide (51); 2-[2-(dimethylamino)phenoxy]-N-(3-methylsulfonylphenyl)- 5-(trifluoromethyl)pyridine-3-carboxamide (52); N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-[2-(trifluoromethyl)phenyl]- (trifluoromethyl)phenoxy]pyridine-3-carboxamide (53); 2-(2,4-dimethoxyphenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (54); N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-(3,4, 5-trifluorophenoxy)pyridine-3-carboxamide (55); 2-(3,5-dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (56); N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-[[6-( Trifluoromethyl-3-pyridyloxypyridine-3-carboxamide (57) ; 2-(1,3-Benzothiazol-4-yloxy)-N-(3-methylsulfonylphenyl) (Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide (58); 2-[4-(difluoromethoxy)phenoxy]-N-[3-(methylsulfonimide) phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (59); 2-(2-chloro-4-fluoro-phenoxy)-N-[3-(methylsulfonimide) phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (60); 2-(2-chloro-4-methoxyphenoxy)-N-[3-(methylsulfonimide) phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (61); 2-(2-chlorophenoxy)-N-[3-(methylsulfonimidoyl)phenyl]- 5-(trifluoromethyl)pyridine-3-carboxamide (62); 2-(2,4-dichlorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl) methyl)pyridine-3-carboxamide (63); 2-[4-(difluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)- (trifluoromethyl)pyridine-3-carboxamide (64); 2-(2-chloro-4-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trimethylsilyl) (trifluoromethyl)pyridine-3-carboxamide (65); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (I)-6-(trifluoromethyl)pyridine-3-carboxamide (66); 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (I)-6-(trifluoromethyl)pyridine-3-carboxamide (67); 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenoxy) (Nyl)-6-(trifluoromethyl)pyridine-3-carboxamide (68); 4-(4-fluoro-2-methoxy-phenoxy)-N-(2-fluoro-5-methylsulfonyl) (6-(trifluoromethyl)-2-phenyl-2-pyridine-3-carboxamide) 9); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-4-(4-fluoro- 2-Methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamine Do(70); 4-(4-fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-6-( (trifluoromethyl)pyridine-3-carboxamide (71); 4-(4-fluoro-2-methoxy-phenoxy)-N-(4-pyridyl)-6-(trimethylsilyl) fluoromethyl)pyridine-3-carboxamide (72); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethyl Amino)-4-pyridyl]-6-(trifluoromethyl)pyridine-3-carboxamide (73); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (phenylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (74) ; 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (phenylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (75 ); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethyl Sulfamoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamine Do(76); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro- 5-Methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carbo oxamide (77); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-pyridyl) -6-(trifluoromethyl)pyridine-3-carboxamide (78); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(4-pyridyl) -6-(trifluoromethyl)pyridine-3-carboxamide (79); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(methylsulfonyl) [sulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide Mido (80); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S- Dimethylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3- Carboxamide (82); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-oxide pyridine) Lysin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxylate Samid (83); 4-(4-fluoro-2-methoxy-phenoxy)-N-(1-oxidepyridine-1- (ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (84 ); 4-(4-fluoro-2-methyl-phenoxy)-N-(1-oxidepyridin-1-yl) Um-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (85) ; 4-[4-(difluoromethoxy)phenoxy]-N-(1-oxidepyridin-1-yl) Um-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (86) ; N-(1-oxidepyridin-1-ium-3-yl)-4-[4-(trifluoromethyl) [oxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (87 ); 4-(2,4-dimethoxyphenoxy)-N-(1-oxidepyridin-1-ium-3 -yl)-6-(trifluoromethyl)pyridine-3-carboxamide (88); 4-(2,4-difluorophenoxy)-N-(1-oxidepyridin-1-ium-3 -yl)-6-(trifluoromethyl)pyridine-3-carboxamide (89); 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinic acid (mido)pyridine-1-oxide (90); N-[3-(methylsulfonimidoyl)phenyl]-4-[4-(trifluoromethacrylamide) [(c)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (91) ; N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-4-[4-(trifluoromethyl)phenyl]-4-[ ... (Oromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide Do (92); 4-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimide) phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (93); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-4-(4-fluoro- 2-Methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide (94); 4-(4-fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trimethyl- (trifluoromethyl)pyridine-3-carboxamide (95); N-pyridazin-4-yl-4-[4-(trifluoromethoxy)phenoxy]-6-( (trifluoromethyl)pyridine-3-carboxamide (96); 4-[4-(difluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)- (trifluoromethyl)pyridine-3-carboxamide (97); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazine-4- yl-6-(trifluoromethyl)pyridine-3-carboxamide (98); 4-(2,4-dimethoxyphenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl) (trimethyl)pyridine-3-carboxamide (99); 4-(2,4-difluorophenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)- (trimethyl)pyridine-3-carboxamide (100); 4-[4-(difluoromethoxy)phenoxy]-N-[3-(methylsulfonimide) [phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (101) ; 4-(2,4-dimethoxyphenoxy)-N-[3-(methylsulfonimidoyl)phenoxy] Nyl]-6-(trifluoromethyl)pyridine-3-carboxamide (102); 4-(2,4-difluorophenoxy)-N-[3-(methylsulfonimidoyl)phenoxy] Nyl]-6-(trifluoromethyl)pyridine-3-carboxamide (103); 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-( (trifluoromethyl)nicotinamide (104); N-(pyridin-3-yl)-4-(4-(trifluoromethoxy)phenoxy)-6- (Trifluoromethyl)nicotinamide (105) 4-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridine-3- yl)-6-(trifluoromethyl)nicotinamide (106); 4-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl) (oromethyl)nicotinamide (107); 4-(2,4-difluorophenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl) (oromethyl)nicotinamide (108); 2-(4-fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridyl) -5-(trifluoromethyl)pyridine-3-carboxamide (109); 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridine- 4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (110); 5-Bromo-2-(4-fluoro-2-methoxyphenoxy)-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (111); 5-Cyclopropyl-2-(4-fluoro-2-methoxyphenoxy)-N-(3-methyl- (Cysulfonylphenyl)pyridine-3-carboxamide (112); 2-(4-fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (113); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro- 2-Methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (114); 2-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimide) [phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (115) ; 2-(4-fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-5-(trimethyl-2-pyridazin-4-yl)- (trifluoromethyl)pyridine-3-carboxamide (116); 2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (117); 2-(4-fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methyl (phenylsulfonylphenyl)pyridine-3-carboxamide (118); 5-chloro-2-(4-fluoro-2-methoxyphenoxy)-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (119); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (1)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide 20); N-(3-methylsulfinylphenyl)-2-[4-(trifluoromethoxy)pheno oxy]-5-(trifluoromethyl)pyridine-3-carboxamide (121); N-(3-sulfamoylphenyl)-2-[4-(trifluoromethoxy)phenoxy] ]-5-(trifluoromethyl)pyridine-3-carboxamide (122); N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethacrylamide) [Ci)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (123 ); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-[4-(trifluoromethyl)phenyl]- (Oromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide Do(124); N-(3-ethylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy] si]-5-(trifluoromethyl)pyridine-3-carboxamide (125); N-(3-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenoxy fluoromethyl)pyridine-3-carboxamide (126); N-(4-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenoxy fluoromethyl)pyridine-3-carboxamide (127); N-pyridazin-4-yl-2-[4-(trifluoromethoxy)phenoxy]-5-( (trifluoromethyl)pyridine-3-carboxamide (128); N-[3-[[dimethyl(oxo)]-λ 6 -sulfanylidene]amino]phenyl]- 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridin ion-3-carboxamide (129); N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethacrylamide) [Ci)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, enanthate Thiomer A (130); N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethacrylamide) [Ci)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, enanthate Thiomer B (131); N-(1-oxidepyridin-1-ium-3-yl)-2-[4-(trifluoromethyl) [Oxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (13 2); 2-(4-fluoro-2-methyl-phenoxy)-N-(1-oxidepyridin-1-yl) Um-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (133 ); 2-(4-fluoro-2-methoxy-phenoxy)-N-(1-oxidepyridine-1- Ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (13 4); 2-(2,4-difluorophenoxy)-N-(1-oxidepyridin-1-ium-3 -yl)-5-(trifluoromethyl)pyridine-3-carboxamide (135); 3-(2-(4-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)di Cotinamide)pyridine 1-oxide (136); 3-(2-(2,4-dimethoxy)phenoxy)-5-(trifluoromethyl)nicotine Amido)pyridine 1-oxide (137); 3-(2-(2-chloro-4-methoxyphenoxy)-5-(trifluoromethyl)nicotinamide tinamide)pyridine 1-oxide (138); 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinic acid (mido)pyridine 1-oxide (139); 2-(2-chloro-4-fluoro-phenoxy)-N-(1-oxidepyridin-1-yl) Umium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (140 ); N-(1-oxidepyridin-1-ium-4-yl)-2-[4-(trifluoromethyl) [Oxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (14 1); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (142 ); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-ethylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (143 ); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S- Dimethylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3- Carboxamide (144); 4-Pyridyl 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-( (trifluoromethyl)pyridine-3-carboxylate (145); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-cyanophenoxy) (Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide (146); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methylpyrrolidone) (4-isopropyl-5-(trifluoromethyl)pyridine-3-carboxamide (14 7); N-(3-carbamoylphenyl)-2-[2-chloro-4-(trifluoromethoxy) phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (148); N-(3-acetylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenyl] [noxy]-5-(trifluoromethyl)pyridine-3-carboxamide (149); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-2 -Oxo-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (150); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethyl (carbamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (151); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (152 ); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (153 ); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethyl Sulfamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamine Do (154); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3,4-difluoromethyl) (fluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (155) ; 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(6-methoxy- 3-Pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (156) ; 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-pyrimidine-5- yl-5-(trifluoromethyl)pyridine-3-carboxamide (157); N-(2-chloro-4-pyridyl)-2-[2-chloro-4-(trifluoromethoxy) phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (158); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(6-fluoro- 3-Pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (159) ; 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(hydroxy [Dimethyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (1 60); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazine-4- yl-5-(trifluoromethyl)pyridine-3-carboxamide (161); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro- 5-Methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carbo oxamide (162); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-fluorophenyl) (phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (163); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-4 -pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (164); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro- 4-Pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (165) ; 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(thiadiazole) -5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (166); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methylpyrrolidone) (3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (16 7); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-5 -methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide Samid (168); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-1 ,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carbohydrate Voxamide (169); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-1 ,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carbohydrate Voxamide (170); 2-(2,4-dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonimide] 171 ); 2-(2,4-dimethoxyphenoxy)-N-[3(methylsulfonimidoyl)phenyl] yl]-5-(trifluoromethyl)pyridine-3-carboxamide (172); 2-(2,4-Dimethoxyphenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl) (trimethyl)pyridine-3-carboxamide (173); 2-(2,4-difluorophenoxy)-N-[3-(methylsulfonimidoyl)phenoxy] Nyl]-5-(trifluoromethyl)pyridine-3-carboxamide (174); 2-(2,4-difluorophenoxy)-N-[3-(N,S-dimethylsulfonimide] 175 ); 2-(2,4-difluorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)- (trimethyl)pyridine-3-carboxamide (176); 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3 -methylsulfonylphenyl)pyridine-3-carboxamide (177); 5-Fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N- (3-Methylsulfonylphenyl)pyridine-3-carboxamide (178); 5-(Difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)-N- (3-Methylsulfonylphenyl)pyridine-3-carboxamide (179); N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethacrylamide) xi)phenoxy]pyridine-3-carboxamide (180); and 5-chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethacrylamide 1)phenoxy]pyridine-3-carboxamide (181) is selected from the group consisting of:

[0053] B. Methods of Treating Conditions, Diseases, or Disorders Associated with Increased Activity or Expression of NaV1.8 ) In some embodiments, the presently disclosed subject matter comprises Na v 1.8 Sodium ion channels A method for modulating a subject in need thereof, comprising administering to said subject a modulating effective amount of a formula The present invention provides a method comprising administering a compound of formula (I).

[0054] In other embodiments, the presently disclosed subject matter comprises Na v 1.8, a method of inhibiting administering to a subject in need thereof an inhibitory effective amount for said subject of a compound of formula (I). A method is provided that includes:

[0055] As used herein, the term "inhibit" and its grammatical derivatives refer to the ability of a compound of the present disclosure, e.g., For example, compounds of the present disclosure of formula (I) may be used to treat Na v 1. Blocking the activity or expression of 8, It refers to the ability to partially block, hinder, reduce or diminish. The term "inhibit" refers to a complete and / or partial reduction in the function of a channel, e.g., at least at least a 10% decrease, and in some embodiments at least a 20%, 30%, 50%, 70%, It is understood that this includes lower reductions, including 5%, 95%, 98% and 100%. Deaf.

[0056] In certain embodiments, the subject matter of the present disclosure is Na v Associated with increased activity or expression of 1.8 In a more particular embodiment, a method for treating a condition, disease, or disorder is provided. v 1. Pathologies, diseases, or disorders associated with increased activity or expression of 8 include pain, particularly inflammatory pain, visceral pain, and pain and neuropathic pain, neurological disorders, in particular multiple sclerosis, autism, in particular Pitt-Hopkins syndrome and psychiatric disorders and combinations thereof, and the method administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof; This includes:

[0057] In certain embodiments, the disease or condition is neuropathic pain, inflammatory pain, visceral pain, cancer pain, or the like. pain, chemotherapy pain, traumatic pain, surgical pain, postoperative pain, childbirth pain, labor pain, neuropathic bladder Bladder, ulcerative colitis, chronic pain, persistent pain, peripheral pain, central pain, chronic headache, migraine , sinus headache, tension headache, phantom limb pain, toothache, peripheral nerve injury or a combination thereof combinations thereof.

[0058] In another embodiment, the disease or condition is HIV-associated pain, HIV treatment-induced neuropathy, rhopecia, trigeminal neuralgia, postherpetic neuralgia, eudynia, heat hypersensitivity, Tosarcoidosis, irritable bowel syndrome, Crohn's disease, Pain associated with MS, amyotrophic lateral sclerosis (ALS), diabetic neuropathies neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis, osteoarthritis, atherosclerotic arthritis Arteriosclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia, malignant hyperthermia, cystic fibrosis, pseudomyositis Aldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression, anxiety, schizophrenia disease, sodium channel toxin-related disease, familial erythromelalgia, primary erythromelalgia, familial erythromelalgia Intestinal pain, cancer, epilepsy, partial and generalized tonic seizures, restless legs syndrome, arrhythmia, fibromuscular Pain, neuroprotection under ischemic conditions caused by stroke or neurotrauma, tachyarrhythmia The present invention is selected from the group consisting of pulmonary embolism, atrial fibrillation and ventricular fibrillation.

[0059] In some embodiments, the disease or condition is Pitt-Hopkins syndrome (PTHS). do.

[0060] The subject matter of the present disclosure includes Na v1.8 Pathological conditions, diseases or disorders associated with increased activity or expression in the manufacture of a medicament for treating a subject suffering from such a disorder, The use of compounds of formula I) is also included.

[0061] The "subject" to be treated by the methods of the present disclosure, in many embodiments thereof, is preferably Although the subject is a human subject, the methods described herein are not intended to be encompassed by the term "subject." It is to be understood that the present invention is effective against all vertebrate species for which it is intended. A "subject" includes a subject receiving treatment for the treatment of an existing condition or disease or to prevent the onset of a condition or disease. human subjects for medical purposes, such as prophylactic treatment for diseases, or for medical, veterinary purposes or development Suitable animal subjects include primates, e.g., humans. cattle, e.g., cattle, bulls, etc.; sheep, e.g., sheep; goats, e.g., pigs, e.g., pigs, adult pigs, etc.; equines, e.g., horses, donkeys, zebras, etc.; feral cats and Cats, including domestic cats; dogs, including domestic dogs; rabbits, including rabbits, hares, etc.; and mice, rats, etc. The animals include, but are not limited to, mammals, including rodents, including transgenic mammals. In some embodiments, the subject may be a fetus, a newborn, a Human subjects include, but are not limited to, infant, juvenile, and adult subjects. A "subject" may include a patient suffering from or suspected of suffering from a condition or disease. Thus, the terms "subject" and "patient" are used interchangeably herein. The term "subject" also refers to an organism, tissue, cell, or collection of cells derived from a subject.

[0062] Generally, an "effective amount" of an active agent or drug delivery device is an amount that elicits a desired biological response. As will be understood by those skilled in the art, an effective amount of a drug or device refers to the amount required to rub the skin. The desired biological endpoint, the agent to be delivered, the composition of the pharmaceutical composition, the target tissue, etc. May vary depending on factors.

[0063] The term "combination" is used in its broadest sense and refers to subjects with at least two more particularly a compound of formula (I) and at least one analgesic; and, optionally and one or more analgesic drugs. More specifically, "in combination" refers to administering The term "combined use" refers to the simultaneous administration of two (or more) active agents, for example, for the treatment of a single condition. As used herein, refers to administering active agents in combination in a single dosage form. The two doses may be administered simultaneously or as separate dosage forms, either on the same day or on different days. They may be administered as separate dosage forms that are administered alternately or sequentially. In another embodiment, the active agents are combined and administered in a single dosage form. (For example, it is desirable to change the amount of one without changing the amount of the other.) The single dosage form may also contain additional active agents for the treatment of a medical condition.

[0064] Furthermore, the compounds of formula (I) described herein may be used alone or in combination with other compounds of formula (I) to enhance the stability of the compounds of formula (I). in combination with an adjuvant that enhances pain relief, alone or in combination with one or more analgesic drugs and in certain embodiments, to facilitate administration of pharmaceutical compositions containing them, and to dissolve or dissolve them. It can increase the amount of soluble fiber, enhance inhibitory activity, and provide adjunctive therapy with other active ingredients. Advantageously, such combination therapy requires lower dosages of the conventional therapeutic agents. Therefore, the potential toxicity and adverse effects of these drugs when used as monotherapy are unknown. Avoid side effects.

[0065] The timing of administration of the compound of formula (I) and the at least one additional therapeutic agent may be adjusted depending on the timing of administration of these agents. As long as the beneficial effects of the combination of The term "in combination" refers to the use of a compound of Formula (I) and at least one additional therapeutic agent in the same It refers to administration either at the time, sequentially, or in combination thereof. Subjects receiving a combination of compound (I) and at least one additional therapeutic agent may receive both As long as the effect of the drug combination is achieved in the subject, the compound of formula (I) and at least The administration of one or more additional therapeutic agents may be at the same time (i.e., simultaneously) or at different times (i.e., The tests may be taken sequentially (in any order, on the same day or on different days).

[0066] When administered sequentially, the drugs should be administered at intervals of 1, 5, 10, 30, 60, 120, 180, 24 In other embodiments, the sequentially administered drugs may be administered within a time period of 0 minutes or more. The agents can be administered within 1, 5, 10, 15, 20 or more days of each other. When a compound of formula (I) and at least one additional therapeutic agent are administered simultaneously, each a separate pharmaceutical composition comprising either a compound of formula (I) or at least one additional therapeutic agent; They can be administered to a subject as a single pharmaceutical composition containing both agents. can be administered to the subject.

[0067] When administered in combination, the effective concentration of each agent to elicit a specific biological response may be lower than the effective concentration of each drug when administered alone, thereby The dose of one or more drugs is increased to a level higher than that required when the drug is administered as a single agent. The effects of multiple drugs can be additive or synergistic, but There need not be any. The drug may be administered multiple times.

[0068] In some embodiments, two or more agents exert a synergistic effect when administered in combination. As used herein, the terms "synergistic effect," "synergistic," and "synergistic "to" and their derivatives, "synergistic effect" or "synergistic combination" or "synergistic combination" "Composition" and the like refer to the biological activity of the combination of a compound of formula (I) and at least one additional therapeutic agent. This refers to a situation in which the biological activity of a drug is greater than the sum of the biological activities of each drug when administered individually.

[0069] The synergy can be expressed as a "synergy index (SI)", which is usually Kull et al., Applied Microbiology 9, 538 (1961) and determine it from the ratio obtained as follows: Can: Q a / Q A + Q b / Q B = Synergy Index (SI) [In the formula, Q A is the concentration of component A acting alone to achieve the endpoint for component A. is the resulting concentration; Q a is the concentration of component A in the mixture that produced the endpoint ; QB is the concentration of component B acting alone to achieve the endpoint for component B. is the resulting concentration; Q b is the concentration of component B in the mixture that produced the endpoint .

[0070] In general, Q a / Q A and Q b / Q B If the sum of these is greater than 1, it indicates antagonism. If the sum is equal to 1, it indicates an additive effect. If the sum is less than 1, it indicates a synergistic effect. The more the number of ingredients in a particular mixture, the greater the synergistic effect that the particular mixture exhibits. than would be expected based on the observed activity of the individual components when used alone. Furthermore, a "synergistically effective amount" of an ingredient refers to, for example, the amount of This refers to the amount of a component required to elicit a synergistic effect in another therapeutic agent.

[0071] More specifically, in some embodiments, the methods of the present disclosure include administering to a subject a compound of formula (I): The compound and / or a pharmaceutically acceptable salt thereof may be selected from the group consisting of one or more of the following compounds: co-administration with one or more compounds selected from: Nonsteroidal anti-inflammatory drugs (NSAIDs), including but not limited to aspirin, diclofenac, Fenac, diflusinal, etodolac, fenbufen, fenoprofen, flufeni Monkeys, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketolo Lac, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, Methulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazo piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac; Opioid analgesics, including but not limited to morphine, heroin, and hydromorphone , oxymorphone, levorphanol, levallorphan, methadone, meperidine, phenytoin Benzyl alcohol, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, promethazine Poxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine fin, butorphanol, nalbuphine and pentazocine; Barbiturates, including but not limited to amobarbital, aprobarbital butabarbital, mephobarbital, methabarbital, methohexital, pen Tobarbital, phenobarbital, secobarbital, talbutal, thiamylal and thiopental; Benzodiazapines, including but not limited to, chlordiazepoxide, clorazep acid, diazepam, flurazepam, lorazepam, oxazepam, temazepam and triazola Mm; Histamine H1 antagonists, including but not limited to diphenhydramine, pyrilamine, Lometazine, chlorpheniramine and chlorcyclizine; Sedatives, such as, but not limited to, glutethimide, meprobamate, methaqualone, and dimethicone Loralphenazone; Skeletal muscle relaxants, such as, but not limited to, baclofen, carisoprodol, chlorzoxy Sazon, cyclobenzaprine, methocarbamol and orphrenazine; NMDA receptor antagonists, such as, but not limited to, dextromethorphan ((+)-3 -hydroxy-N-methylmorphinan) or its metabolite dextrorphan (( +)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline phosphoquinine, cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, morphine and dextromethorphan) combination preparations), topiramate, neramexane or perzinfo containing an NR2B antagonist esters such as ifenprodil, traxoprodil and (-)-(R)-6-{2-[ 4-(3-fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxy Ethyl-3,4-dihydro-2(1H)-quinolinone; transient receptor potential ion channel antagonists; α-adrenergic agonists, such as, but not limited to, doxazosin, tamsulosin, clozapine, nidin, guanfacine, dexmetatomidine, modafinil and 4-amino-6,7- Dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinoline (2-pyridyl)-5-(2-pyridyl)quinazoline; Tricyclic antidepressants, including but not limited to desipramine, imipramine, amitriptyline phosphorus and nortriptyline; Anticonvulsants, such as, but not limited to, carbamazepine (Tegretol®) , lamotrigine, topiramate, lacosamide (Vimpat®) and valproate et; Tachykinin antagonists, particularly NK-3, NK-2 or NK-1 antagonists, including but not limited to (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9, 10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4 ]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione (TAK-6 37), 5-[[(2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethyl) methyl)phenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl ethyl]-1,2-dihydro-3H-1,2,4-triazol-3-one (MK-869 ), aprepitant, ranepitant, dapitant and 3-[[2-methoxy-5-(trimethylsilyl) Fluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine (2S,3S ); Muscarinic antagonists, including but not limited to, oxybutynin, tolterodine, propivecin, Phosphorus, trospium chloride, darifenacin, solifenacin, temiverine and ipratro pium; Cyclooxygenase-2 selective (COX-2) inhibitors, including but not limited to, cerebrospinal fluid (CF) inhibitors, Coxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib Xib and lumiracoxib; Coal tar analgesics, including but not limited to paracetamol; Neuroleptics, including but not limited to, droperidol, chlorpromazine, haloperidol perphenazine, thioridazine, mesoridazine, trifluoperazine, fluphenazine gin, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertipine ndole, aripiprazole, sonepiprazole, blonanserin, iloperidone, peronam Spiron, raclopride, zotepine, bifeprunox, asenapine, lurasidone, Misulpride, Balaperidone, Parindol, Eplivanserin, Osanetant, Rimona Ban, meclineltant, Miraxion® and sarizotan; Vanilloid receptor agonists, such as, but not limited to, resiniferatoxin or civamide ; Vanilloid receptor antagonists, such as, but not limited to, capsazepine, GRC-15300 ; β-adrenergic agonists, including but not limited to, propranolol; Local anesthetics, such as, but not limited to, mexiletine; Corticosteroids, including but not limited to, dexamethasone and prednisone; 5-HT receptor agonists or antagonists, particularly 5-HT1B / 1D agonists, such as, but not limited to, However, eletriptan, sumatriptan, naratriptan, zolmitriptan or rizatriptan Liptan; 5-HT2A receptor antagonists, such as, but not limited to, R(+)-α-(2,3-dimethicone) (2-(4-fluorophenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methoxide Nol (MDL-100907), eplivanserin, ketanserin, and pimavanserin ; Cholinergic (nicotinic) analgesics, such as, but not limited to, ispronicline (TC -1734), (E)-N-methyl-4-(3-pyridinyl)-3-buten-1-amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridin nicotine (ABT-594); α2δ ligands, such as, but not limited to, gabapentin (Neurontin®) gabapentin GR (Gralise®), gabapentin enacarbil (Horizant®), pregabalin (Lyrica®), 3- Methylgabapentin, (1[α],3[α],5[α])(3-amino-methyl-bis(methyl) (3S,5R)-3-aminomethyl-5-[3.2.0]hept-3-yl]acetic acid Methyl-heptanoic acid, (3S,5R)-3-amino-5-methyl-heptanoic acid, (3S, 5R)-3-amino-5-methyl-octanoic acid, (2S,4S)-4-(3-chlorophenoxy) (2S,4S)-4-(3-fluorobenzyl)proline, [(1R ,5R,6S)-6-(aminomethyl)bicyclo[3.2.0]hept-6-yl]acetic acid , 3-(1-aminomethyl-cyclohexylmethyl)-4H-[1,2,4]oxadia zole-5-one, C-[1-(1H-tetrazol-5-ylmethyl)-cycloheptyl methylamine, (3S,4S)-(1-aminomethyl-3,4-dimethyl-cyclo Pentyl)-acetic acid, (3S,5R)-3-aminomethyl-5-methyl-octanoic acid, (3 S,5R)-3-amino-5-methyl-nonanoic acid, (3S,5R)-3-amino-5-methyl-nonanoic acid octanoic acid, (3R,4R,5R)-3-amino-4,5-dimethyl-heptanoic acid and (3R,4R,5R)-3-amino-4,5-dimethyl-octanoic acid; Cannabinoid receptor ligands, such as, but not limited to, cannabidiol KHK-6 188; metabotropic glutamate subtype 1 receptor antagonists; Serotonin reuptake inhibitors, such as, but not limited to, sertraline, sertraline derivatives Demethylsertraline, fluoxetine, norfluoxetine (fluoxetine desmethylsertraline) methyl metabolites), fluvoxamine, paroxetine, citalopram, citalopram metabolites Submethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine , ifoxetine, cyanodothiepin, ritoxetine, dapoxetine, nefazodone, se Lycuramine and Trazodone; noradrenaline (norepinephrine) reuptake inhibitors, including but not limited to, Protiline, lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxa Cetin, mianserin, buproprion, buproprion metabolite hydroxybuproprion , nomifensine and viloxazine (Vivalan®), especially selective norfloxacin Adrenaline reuptake inhibitors, such as reboxetine, especially (S,S)-reboxetine; Dual serotonin-noradrenaline reuptake inhibitors, such as, but not limited to, Benla Venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine , clomipramine metabolite desmethylclomipramine, duloxetine (Cymbalta (R), milnacipran and imipramine; Rho kinase inhibitors; Inducible nitric oxide synthase (iNOS) inhibitors, such as, but not limited to, S-[2-[ (1-Iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(l-iminoethyl)amino]ethyl]-L-homocysteine S-[2-[(1- Iminoethyl)amino]ethyl]-2-methyl-L-cysteine, (2S,5Z)-2- Amino-2-methyl-7-[(l-iminoethyl)amino]-5-heptenoic acid, 2-[[ (1R,3S)-3-amino-4-hydroxy-1-(5-thiazolyl)butyl]thio] -S-chloro-S-pyridinecarbonitrile;2-[[(1R,3S)-3-amino-4 -hydroxy-1-(5-thiazolyl)butyl]thio]-4-chlorobenzonitrile, ( 2S,4R)-2-amino-4-[[2-chloro-5-(trifluoromethyl)phenyl ]thio]-5-thiazolylbutanol, 2-[[(1R,3S)-3-amino-4-hydroxybenzoate [1-(5-thiazolyl)butyl]thio]-6-(trifluoromethyl)-3-pyridyl Lysinecarbonitrile, 2-[[(1R,3S)-3-amino-4-hydroxy-1-( 5-Thiazolyl)butyl]thio]-5-chlorobenzonitrile, N-[4-[2-(3- Chlorobenzylamino)ethyl]phenyl]thiophene-2-carboxamidine, NXN -462 and guanidinoethyl disulfide; Acetylcholinesterase inhibitors, including but not limited to donepezil; Prostaglandin E2 subtype 4 antagonists, such as, but not limited to, N-[({2- [4-(2-ethyl-4,6-dimethyl-1H-imidazo[4,5-c]pyridine-1- phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide and and 4-[(15)-1-({[5-chloro-2-(3-fluorophenoxy)pyridine- 3-yl]carbonyl}amino)ethyl]benzoic acid; Leukotriene B4 antagonists, such as, but not limited to, 1-(3-biphenyl-4-yl)benzoate Methyl-4-hydroxy-chroman-7-yl)-cyclopentanecarboxylic acid (CP-1 05696), 5-[2-(2-carboxyethyl)-3-[6-(4-methoxyphenyl) [5E-hexenyl]oxyphenoxy]valeric acid (ONO-4057) and DPC -11870; 5-lipoxygenase inhibitors, such as, but not limited to, zileuton, 6-[(3-fluorouracil, 5-hydroxybenzoates ... Oro-5-[4-methoxy-3,4,5,6-tetrahydro-2H-pyran-4-yl] )phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138) and 2,3,5 -Trimethyl-6-(3-pyridylmethyl)-1,4-benzoquinone (CV-6504) ; Sodium channel blockers, including but not limited to, lidocaine, lidocaine plus tetrahydrocanthoate Cain cream (ZRS-201) and eslicarbazepine acetate; 5-HT3 antagonists, such as, but not limited to, ondansetron; N-methyl-D-aspartate receptor antagonists; Voltage-dependent calcium channel blockers (e.g., N-type and T-type), including, but not limited to, However, diconctide, Z-160, (R)-2-(4-cyclopropylphenyl)-N-( 1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)acetoacetate amide; KCNQ openers (e.g., KCNQ2 / 3(K v 7.2 / 3)); TPRV 1 receptor agonists, such as, but not limited to, capsaicin (Neuroges (R), Qutenza(R); and pharmaceutically acceptable salts and solutions thereof. solvate; Nicotinic receptor antagonists, including but not limited to varenicline; Nerve growth factor antagonists, including but not limited to, tanezumab; endopeptidase stimulators, such as, but not limited to, senrebotase; Angiotensin II antagonists, such as, but not limited to, EMA-401; Tramadol®, tramadol ER (Ultram ER®) , tapentadol ER (Nucynta®); PDE5 inhibitors, such as, but not limited to, 5-[2-ethoxy-5-(4-methyl-1 -piperazinyl-sulfonyl)phenyl]-1-methyl-3-n-propyl-1,6-di Hydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6 R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3 ,4-methylenedioxyphenyl)-pyrazino[2´,1´:6,1]-pyrido[3,4 -b]indole-1,4-dione (IC-351 or tadalafil), 2-[2-ethoxybenzone 5-(4-ethyl-piperazin-1-yl-1-sulfonyl)-phenyl]-5- Methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazine-4- vardenafil, 5-(5-acetyl-2-butoxy-3-pyridinyl)-3- Ethyl-2-(1-ethyl-3-azetidinyl)-2,6-dihydro-7H-pyrazolo [4,3-d]pyrimidin-7-one, 5-(5-acetyl-2-propoxy-3-pyrimidin-7-one) 3-ethyl-2-(1-isopropyl-3-azetidinyl)-2,6-dihydriodide 5-[2-ethoxy-5-(4-pyrazolo[4,3-d]pyrimidin-7-one]-2H-pyrazolo[4,3-d]pyrimidin-7-one] -ethylpiperazin-1-ylsulfonyl)pyridin-3-yl]-3-ethyl-2-[ 2-Methoxyethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine- 7-one, 4-[(3-chloro-4-methoxybenzyl)amino]-2-[(2S)-2 -(hydroxymethyl)pyrrolidin-1-yl]-N-(pyrimidin-2-ylmethyl) Pyrimidine-5-carboxamide, 3-(1-methyl-7-oxo-3-propyl-6, 7-Dihydro-1H-pyrazolo[4,3-d]pyrimidin-5-yl)-N-[2-(1 -methylpyrrolidin-2-yl)ethyl]-4-propoxybenzenesulfonamide; Na V1.7 Blockers, such as, but not limited to, XEN-402, XEN403, TV- 45070, PF-0509771, CNV1014802, GDC-0276, RG7 893 and WO 2011 / 140425; WO 2012 / 106499 ;WO 2012 / 112743;WO 2012 / 125613, WO Patent Publication No. 2012 / 116440, International Publication No. 2011026240, U.S. Pat. No. 8,888,626 No. 83,840 or No. 8,466,188 or PCT / US2013 / 21535 The entire contents of each application are incorporated by reference; and Na V 1.7 Blockers, such as, but not limited to, 2-benzylspiro[3,4-dihydro Pyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl)-(4-isopropyl) 2,2,2-trifluoro-1-[1'- [3-Methoxy-4-[2-(trifluoromethoxy)ethoxy]benzoyl]-2,4 -dimethyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperazine Lysine]-6-yl]-ethanone, [8-fluoro-2-methyl-6-(trifluoromethyl)- thyl)spiro[3,4-dihydropyrrolo[1-,2-a]pyrazine-1,4'-piperidinyl 1-(4-isobutoxy-3-methoxyphenyl)methanone, 1-( 4-Benzhydrylpiperazin-1-yl)-3-[2-(3,4-dimethylphenoxy) )ethoxy]propan-2-ol, 4-butoxy-3-methoxy-phenyl)-[2- Methyl-6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pi razine-1,4'-piperidin]-1'-yl]methanone, [8-fluoro-2-methyl -6-(trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine phenyl-1,4'-piperidin-1'-yl]-(5-isopropoxy-6-methyl-2- pyridyl)methanone, (4-isopropoxy-3-methyl-phenyl)-[2-methyl- 6-(1,1,2,2,2-pentafluoroethyl)spiro[3,4-dihydropyrrolo[ 1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 5-[2-methyl 4-[2-methyl-6-(2,2,2-trifluoroacetyl)spiro[3,4- Dihydropyrrolo-[1,2-a]pyrazine-1,4'-piperidine]-1'-carbonyl ]phenyl]pyridine-2-carbonitrile, (4-isopropoxy-3-methyl-phenyl Nyl)-[6-(trifluoromethyl)spiro[3,4-dihydro-2H-pyrrolo[1, 2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 2,2,2-tri Fluoro-1-[1'-[3-methoxy-4-[2-(trifluoromethoxy)ethoxy ]benzoyl]-2-methyl-spiro[3,4-dihydropyrrolo[1,2-a]pyrazine -1,4'-piperidin]-6-yl]ethanone, 2,2,2-trifluoro-1-[1 '-(5-Isopropoxy-6-methyl-pyridine-2-carbonyl)-3,3-dimethyl Chil-spiro[2,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine ]-6-yl]ethanone, 2,2,2-trifluoro-1-[1´-(5-isopentyl Oxypyridine-2-carbonyl)-2-methyl-L-spiro[3,4-dihydropyrrolo [1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, (4-isopropyl (2-methyl-6-(trifluoromethyl)spiroxyl-3-methoxyphenyl)-[2-methyl-6-(trifluoromethyl)spiroxyl-3-methoxyphenyl]spiroxyl 1,4'-piperidine-3,4-dihydropyrrolo[1,2-a]pyrazine yl]methanone, 2,2,2-trifluoro-1-[1'-(5-isopentyloxypyridine Lysine-2-carbonyl)-2,4-dimethyl-spiro[3,4-dihydropyrrolo[1, 2-a]pyrazine-1,4'-piperidin]-6-yl]ethanone, 1-[(3S)-2 ,3-dimethyl-1'-[4-(3,3,3-trifluoropropoxymethyl)benzoyl spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4´-piperidine] -6-yl]-2,2,2-trifluoro-ethanone, 8-fluoro-2-methyl-6- (trifluoromethyl)spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1, 4'-piperidin]-1'-yl]-[3-methoxy-4-[(1R)-1-methylpropional [2,2,2-trifluoro-1-[1'-(5-isopropyl]phenyl]methanone (6-methyl-pyridine-2-carbonyl)-2,4-dimethyl-spiro[3,4 -Dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidin]-6-yl]ethano 1-[1'-[4-methoxy-3-(trifluoromethyl)benzoyl]-2-methyl -spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4'-piperidine] -6-yl]-2,2-dimethyl-propan-1-one, (4-isopropoxy-3-methyl- 2-methyl-6-(trifluoromethyl)spiro[3,4-dihydro- pyrrolo[1,2-a]pyrazine-1,4'-piperidin]-1'-yl]methanone, 2 -methyl-6-(1-methylcyclopropanecarbonyl)spiro[3,4-dihydropyrro 2-[1,2-a]-pyrazine-1,4'-piperidin]-1'-yl]-[4-(3,3 ,3-trifluoropropoxymethyl)phenyl]methanone, 4-bromo-N-(4-bromo bromophenyl)-3-[(1-methyl-2-oxo-4-piperidyl)sulfamoyl] benzamide or (3-chloro-4-isopropoxy-phenyl)-[2-methyl-6- (1,1,2,2,2-pentafluoroethyl)spiro[34-dihydropyrrolo[1,2 -a]pyrazine-1,4´-piperidin]-1´-yl]methanone.

[0072] In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound described herein. or a pharmaceutically acceptable salt thereof, with or without a pharmaceutically acceptable carrier, Selected from the group consisting of minophen, NSAIDs, opioid analgesics and combinations thereof This includes administering the compound in combination with a second therapeutic agent that is also administered.

[0073] In some embodiments, the method comprises administering to a subject a therapeutically effective amount of a compound described herein. or a pharmaceutically acceptable salt thereof, with or without a pharmaceutically acceptable carrier, In one embodiment, the compound is administered in combination with an additional therapeutic agent for treating multiple pain conditions. In this case, additional treatments include acetaminophen, NSAIDs (aspirin, ibuprofen, and and naproxen) and opioid analgesics. In another embodiment, the additional therapeutic agent is acetaminophen. In another embodiment, the additional therapeutic agent is an opioid analgesic.

[0074] C. Pharmaceutical Compositions and Administration In another aspect, the present disclosure provides a compound of formula (I) alone or in combination with one or more additional compounds. and providing a pharmaceutical composition comprising the compound in combination with an additional therapeutic agent in admixture with a pharmaceutically acceptable excipient. Those skilled in the art will recognize that pharmaceutical compositions include pharmaceutically acceptable salts of the compounds described above. It will be recognized that pharmaceutically acceptable salts are generally well known to those skilled in the art and are included herein. Relatively non-toxic acids or bases, depending on the specific substituent moieties found on the compounds described in the specification When the compounds of the present disclosure contain a relatively acidic functional group, the salts of the active compounds may be prepared by the following procedure. The neutral form of such a compound can be reacted with a sufficient amount of the desired base, either neat or in a suitable solution. One of the ionic complexes by contacting either in an active solvent or by ion exchange. By replacing the basic counterion (base) of Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, Examples of suitable salts include ammonium, ammonium, organic amino or magnesium salts or similar salts.

[0075] When compounds of the present disclosure contain relatively basic functional groups, the neutral forms of such compounds may be contacting the compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid. or by ion exchange, replacing one acidic counterion (acid) of an ionic complex with another. By replacing the acid, an acid addition salt can be obtained. Examples of pharmaceutically acceptable acid addition salts Examples include hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, monohydrogen phosphate, and phosphoric acid. Salts derived from inorganic acids such as dihydrogen, sulfuric, monohydrogen sulfate, hydroiodic or phosphoric acid, as well as acetic acid, propanol, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, Salts derived from relatively non-toxic organic acids such as enoic acid, tartaric acid, methanesulfonic acid, and the like are included. Salts of amino acids such as arginate and salts of organic acids such as glucuronic acid or galacturonic acid are also suitable. (e.g., Berge et al., “Pharmaceutical Sa lts´´, Journal of Pharmaceutical Science , 1977, 66, 1-19). Certain compounds of the present disclosure may be prepared by converting the compounds into salts. Basic and acidic functional groups that allow conversion into either base or acid addition salts The term "group" includes both groups.

[0076] Thus, pharmaceutically acceptable salts suitable for use with the subject matter of the present disclosure include, but are not limited to, Examples of salts that are not suitable for use include acetate, benzenesulfonate, benzoate, bicarbonate, and bitartrate. Salt, bromide, calcium edetate, camsylate, carbonate, citrate, edetate, ethoxylated Disilate, estolate, esilate, fumarate, gluceptate, gluconate, Glutamate, Glycolyl Arsanilate, Hexyl Resorcinate, Hydrabamine, Hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, Lactobionate, malate, maleate, mandelate, mesylate, mucate , napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate Phosphate, polygalacturonate, salicylate, stearate, acetate, succinate Other pharmaceutically acceptable salts include hydroxybenzoates, ... The salts used are described, for example, in Remington: The Science and Practice Tice of Pharmacy (20th ed.) Lippincott, This can be seen in Williams & Wilkins (2000).

[0077] In therapeutic and / or diagnostic applications, the compounds of the present disclosure may be used in both systemic and topical or localized applications. The techniques and formulations are generally as described in Rem. ington: The Science and Practice of Phar macy (20th ed.) Lippincott, Williams & W This can be seen in ilkins (2000).

[0078] Depending on the particular condition being treated, such agents may be formulated into liquid or solid dosage forms, and The agent can be administered internally or topically, as known to those skilled in the art, for example: It can be delivered in a timed or sustained release form. Techniques for formulation and administration are , Remington: The Science and Practice of Pharmacy (20th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes include oral administration, Buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or enteral administration; intramuscular , subcutaneous, intramedullary injection and intrathecal, direct intraventricular, intravenous, intraarticular, intrasternal, intrasynovial, intrahepatic, Parenteral delivery, including intralesional, intracranial, intraperitoneal, intranasal, or intraocular injection or other modes of delivery. Examples include:

[0079] For injection, the agents of the present disclosure are administered in a suitable solution such as Hank's solution, Ringer's solution, or physiological saline buffer. They can be formulated and diluted in aqueous solutions, such as physiologically compatible buffers. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Permeabilizing agents are generally known in the art.

[0080] The compounds disclosed herein can be used to practice the disclosure using a pharmaceutically acceptable inert carrier. It is within the scope of this disclosure to formulate the compound into a dosage suitable for systemic administration. By appropriate selection and appropriate manufacturing practices, the compositions of the present disclosure, particularly those formulated as solutions, can be readily obtained. The compound can be administered parenterally, for example, by intravenous injection. The compound is formulated into a dosage suitable for oral administration using pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the present disclosure to be easily formulated into therapeutically effective pharmaceutical compositions. The composition may be in the form of a tablet, pill, capsule, liquid, gel, or the like, to be taken orally by a subject (e.g., a patient). The composition can be formulated as a solution, syrup, slurry, suspension, or the like.

[0081] For nasal or inhalation delivery, the medicaments of the present disclosure can be formulated by methods known to those skilled in the art. It can be used in the form of a solubilizing, diluting or dispersing agent, such as saline; benzyl alcohol; preservatives such as ethanol; absorption enhancers; and fluorocarbons, etc. Not limited to.

[0082] Pharmaceutical compositions suitable for use in the present disclosure include compositions containing the active ingredient in a concentration sufficient to achieve its intended purpose. The determination of an effective amount is particularly described in the methods provided herein. This is well within the capabilities of those skilled in the art in light of the detailed disclosure provided herein. The compounds of the present invention are effective over a wide dosage range. For example, in the treatment of adults, 0.01-1000mg, 0.5-100mg, 1-50mg per day and 5- A dosage of 40 mg is an example of a dosage that may be used. Non-limiting dosages are The exact dosage depends on the route of administration, the form in which the compound is administered, and the type of treatment being administered. the subject receiving the treatment, the weight of the subject receiving the treatment, the bioavailability of the compound(s), Absorption, distribution, metabolism, and excretion (ADME), toxicity, and physician selection of the compound(s). It depends on the choice and experience.

[0083] In addition to the active ingredient, these pharmaceutical compositions contain a compound that is capable of converting the active compound into a pharmaceutically usable preparation. It contains a suitable pharmaceutically acceptable carrier, including excipients and auxiliaries that facilitate processing. Preparations formulated for oral administration may be tablets, dragees, capsules or solutions. The form may be:

[0084] Pharmaceutical preparations for oral use comprise an active compound in combination with a solid excipient, optionally obtained The resulting mixture is milled, and if necessary, suitable auxiliaries are added, and the granulated mixture is then processed. Suitable excipients are, in particular, lactose, lactic acid bacteria ... sugars such as sucrose, mannitol or sorbitol; cellulose preparations; For example, corn starch, wheat starch, rice starch, potato starch, gelatin Chin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, Sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PV P: povidone) and other fillers. If necessary, cross-linked polyvinylpyrrolidone, A disintegrating agent such as agar, alginic acid, or a salt thereof such as sodium alginate may be added. This can be done.

[0085] Dragee cores are provided with a suitable coating. For this purpose, concentrated sugar solutions are used. This solution may optionally contain gum arabic, talc, polyvinylpyrrolidone, Rolidone, Carbopol Gel, Polyethylene Glycol (PEG) and / or Titanium Dioxide The active compound may contain a solvent, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyestuffs or pigments may be added to the tablets or dragee coatings to identify or characterize various combinations. can be added to the ting.

[0086] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin and gelatin capsules. Examples include soft, sealed capsules made of plaster and a plasticizer such as glycerol or sorbitol. Push-fit capsules contain the active ingredients, filler such as lactose, binders such as starch, etc. a filler and / or lubricant such as talc or magnesium stearate, and optionally In soft capsules, the active compound may be mixed with fatty oils, fluid powders, or other suitable ingredients. Dissolved or suspended in a suitable liquid such as polyethylene glycol (PEG) or liquid In addition, stabilizers can be added.

[0087] (II. Definition) Although specific terms are used herein, they are used in a generic and descriptive sense only. Unless otherwise defined, the terms used herein are used in their entirety and are not intended to be limiting. All technical and scientific terms used herein are understood to be within the skill of the art to which the subject matter described herein belongs. has the same meaning as commonly understood by those skilled in the art.

[0088] The following terms relating to compounds of formula (I) are believed to be well understood by those skilled in the art: However, to facilitate explanation of the subject matter of this disclosure, the following definitions are provided: are intended to supplement and explain definitions that would be apparent to one of skill in the art upon review of this disclosure. and is not intended to exclude.

[0089] As used herein, substituted (whether preceded by the word "optionally" or not) The terms aryl, aryl, aryl(s) and substituents, as understood by those skilled in the art, refer to all atoms. The ability to change one functional group on a molecule to another, provided that the valence of the molecule is maintained. Multiple positions in any given structure may contain multiple substitutions selected from a particular group. When a group can be substituted, the substituents can be the same or different at every position. Substituents may also be further substituted (e.g., some aryl substituents may have one or more substituted groups). The aryl group may have other substituents, such as another aryl group further substituted with an aryl group.

[0090] When a substituent or linking group is designated by a conventional chemical formula written from left to right, it These equally encompass chemically identical substituents that result when the structure is written from right to left. For example, -CH2O- is equivalent to -OCH2-; -C(=O)O- is equivalent to -O -C(=O)- is equivalent to -OC(=O)NR- is equivalent to -NRC(=O)O- , etc.

[0091] When the term "independently selected" is used, the substituents being referred to (e.g., group R1) , R groups such as R2 or variables such as "m" and "n") may be the same or different. For example, both R1 and R2 may be substituted alkyl, or R1 may be hydrogen and R2 may be substituted alkyl. may be a substituted alkyl, etc.

[0092] The terms "a," "an," or "a(n)" are used herein to refer to groups of substituents. When a compound is "an" alkyl or aryl, it means at least one. When substituted with, the compound optionally contains at least one alkyl and / or at least one In addition, if the site is substituted with an R substituent, When a moiety is R-substituted, the moiety must have at least one and is substituted with two R substituents, each R substituent being optionally different.

[0093] A named "R" or group will generally be referred to by its name unless otherwise specified herein. The resulting group will have a structure recognized in the art as corresponding to a group having the formula: For purposes of this, certain representative "R" groups as defined above are defined below.

[0094] The description of compounds of the present disclosure is limited by principles of chemical bonding known to those skilled in the art. Thus, if a group may be substituted with one or more of several substituents, such The substituents conform to the principles of chemical bonding and are not inherently unstable compounds and / or hydrophilic. It is likely to be unstable under ambient conditions, including neutral and some known physiological conditions. It is selected to provide a compound that would be known to one skilled in the art. For example, heterocyclo Alkyl or heteroaryl may be bonded to the ring helices according to principles of chemical bonding known to those skilled in the art. It is attached to the rest of the molecule through a heteroatom, thereby circulating an inherently unstable compound. Avoid.

[0095] Unless expressly defined otherwise, "substituents" as used herein are defined herein. The functional group comprises one or more of the following moieties:

[0096] As used herein, the term "hydrocarbon" refers to any chemical group containing hydrogen and carbon. The hydrocarbon may be substituted or unsubstituted. As such, when substitutions are made, all valences must be satisfied. can be unsaturated, saturated, branched, unbranched, cyclic, polycyclic, or heterocyclic. Hydrogen is further defined herein below and includes, for example, methyl, ethyl, n-propyl, propyl, and propyl groups. isopropyl, cyclopropyl, allyl, vinyl, n-butyl, tert-butyl, ethynyl cyclohexyl, and the like.

[0097] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, , straight chain (i.e., unbranched) or branched chain, acyclic or cyclic hydrocarbon groups or combinations thereof, which may be fully saturated or mono- or polyunsaturated. may be a sum, and may include divalent and polyvalent groups, and may have the specified number of carbon atoms. (i.e., C 1-10 contains 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 carbons In certain embodiments, the term "alkyl" refers to 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 39, , 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 1 C containing 8, 19 and 20 carbons 1-20Within 1000 kJ / min, linear (i.e., "straight-chain"), Branched or cyclic, saturated or at least partially unsaturated, in some cases fully unsaturated ( alkenyl and alkynyl) from hydrocarbon moieties containing 1 to 20 carbon atoms. It is a hydrocarbon radical obtained by removing one hydrogen atom from

[0098] Representative saturated hydrocarbon groups include methyl, ethyl, n-propyl, isopropyl, and n -butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl pentyl, isopentyl, neopentyl, n-hexyl, sec-hexyl, n-heptyl , n-octyl, n-decyl, n-undecyl, dodecyl, cyclohexyl, (cyclohexyl) cyclopropylmethyl, cyclopropylmethyl, and their homologs and isomers. , but not limited to these.

[0099] "Branched" means that a lower alkyl group such as methyl, ethyl, or propyl is not part of a linear alkyl chain. "Lower alkyl" refers to an alkyl group having 1 to about 8 carbon atoms, e.g., For example, alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms (i.e., C "Higher alkyl" refers to alkyl groups having from about 10 to about 20 carbon atoms, e.g., For example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms In certain embodiments, "alkyl" refers to, in particular, C1-C8 alkyl groups. In another embodiment, "alkyl" refers to, in particular, C1-C8 branched chain alkyl. Refers to Kill.

[0100] The alkyl group is optionally substituted with one or more alkyl group substituents ("substituted alkyl"). The term "alkyl substituted" may be used interchangeably with "alkyl group substituted" or "alkyl substituted" and may be the same or different. The "group" includes alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, arylamino ... Aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkyl These include arylalkylthio, carboxyl, alkoxycarbonyl, oxo and cycloalkyl. Optionally, one or more oxygen atoms along the alkyl chain may be present, but are not limited to: , sulfur, or a substituted or unsubstituted nitrogen atom (the nitrogen substituents are hydrogen, lower alkyl (as defined in the present invention) The term "alkylaminoalkyl" is used herein to refer to an alkyl group containing an aryl group. This can be done.

[0101] Thus, as used herein, the term "substituted alkyl" refers to any group as defined herein. The alkyl group may include one or more atoms or functional groups of the alkyl group, such as Alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl Sil, nitro, amino, alkylamino, dialkylamino, sulfate, cyano and It is substituted with another atom or functional group, including mercapto.

[0102] The term "heteroalkyl", by itself or in combination with another term, means any heteroalkyl group, unless otherwise specified. As long as the carbon atom or hetero atom is a stable straight or branched chain, A cyclic hydrocarbon group having 3 to 10 carbon atoms or hetero atoms, or a combination thereof and at least one carbon atom and an atom selected from the group consisting of O, N, P, Si, and S. At least one heteroatom (nitrogen, phosphorus and sulfur atoms) is optionally oxidized. and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) O, N, P and S and Si may be present in any heteroalkyl group. It may be placed at any interior position or at the position at which the alkyl group is attached to the remainder of the molecule. For example, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -C H2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH 2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-OC H3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3 )-CH3, O-CH3, -O-CH2-CH3 and -CN. For example, -CH2-NH-OCH3 and -CH2-O-Si(CH3) There may be up to two or three heteroatoms consecutive, such as 3.

[0103] As noted above, heteroalkyl groups as used herein include, but are not limited to, —C(O)NR′, —NR Heteroatoms such as -R, -OR, -SR, -S(O)R and / or -S(O2)R The term "heteroalkyl" includes groups that are attached to the rest of the molecule via a bond. , followed by a specific heteroalkyl group such as -NR'R, It is understood that the terms -NR´R´´ are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Therefore, the term "heteroalkyl" is used herein to refer to certain heteroalkyl groups such as -NR'R'. This should not be construed as excluding teraalkyl groups.

[0104] "Cyclic" and "cycloalkyl" refer to groups having from about 3 to about 10 carbon atoms, e.g., 3, 4, 5 refers to a non-aromatic monocyclic or polycyclic ring system having 6, 7, 8, 9 or 10 carbon atoms. The cycloalkyl group may optionally be partially unsaturated. The alkyl group may optionally be an alkyl group substituent, oxo and / or alkyl, as defined herein. Along the cyclic alkyl chain, optionally one or more acids may be substituted. a nitrogen atom, sulfur, or a substituted or unsubstituted nitrogen atom (nitrogen substituents are hydrogen, unsubstituted alkyl, substituted alkyl, aryl, or substituted aryl) can be inserted, thereby Representative monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, Polycyclic cycloalkyl rings include adamantyl, cyclohexyl, and cycloheptyl. octahydronaphthyl, decalin, camphor, camphane and noradamantyl and di and fused ring systems such as hydronaphthalene and tetrahydronaphthalene.

[0105] As used herein, the term "cycloalkylalkyl" refers to a cycloalkyl group as defined herein. a cycloalkyl group, also as defined above, including the alkylene moiety, e.g., C 1-20 Al Refers to a cycloalkyl group attached to the parent molecular moiety through an alkylene moiety. Examples of alkyl groups include cyclopropylmethyl and cyclopentylethyl.

[0106] The terms "cycloheteroalkyl" or "heterocycloalkyl" refer to a non-aromatic ring system , unsaturated or partially unsaturated ring systems, such as 3-10 membered substituted or unsubstituted cycloalkyl A ring system containing one or more heteroatoms, the heteroatoms being the same or different. It may contain nitrogen (N), oxygen (O), sulfur (S), phosphorus (P) and silicon (Si). and a ring system selected from the group consisting of: Point.

[0107] The cycloheteroalkyl ring may optionally be joined to other cycloheteroalkyl rings and / or non-aromatic rings. The heterocycle may contain oxygen, and those having 1 to 3 heteroatoms independently selected from sulfur and nitrogen, In the case of In certain embodiments, the term heterocyclic refers to at least one of At least one ring atom is a heteroatom selected from O, S and N (nitrogen and sulfur heteroatoms) is optionally oxidized) refers to a group having 1 to 3 hetero atoms independently selected from, but not limited to, oxygen, sulfur, and nitrogen. Bicyclic or tricyclic groups containing fused six-membered rings with 5-membered rings are included, and (i) each five-membered ring has 0 to 2 each 6-membered ring has 0 to 2 double bonds, and each 7-membered ring has 0 to 3 double bonds. (ii) the nitrogen and sulfur heteroatoms may be optionally oxidized; i) the nitrogen heteroatom may be optionally quaternized; and (iv) any of the above heterocycles. The cycloheteroaryl ring may be fused to an aryl or heteroaryl ring. The alkyl ring system includes pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazoline, Lysinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, quinuclidinyl morpholinyl, thiomorpholinyl, thiadiazinanyl, tetrahydrofuranyl, etc. Examples include, but are not limited to:

[0108] The terms "cycloalkyl" and "heterocycloalkyl" may be used by themselves or with other In combination with the terms "alkyl" and "heteroalkyl," respectively, unless otherwise specified. Furthermore, in the case of heterocycloalkyl, the heteroatom is a heterocyclic group. The ring can occupy any position that attaches it to the rest of the molecule. Examples of cycloalkyl include: is cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, Examples of heterocycloalkyl include, but are not limited to, cycloheptyl, etc. Examples include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, and 2-piperidine. Lysinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuranoyl tetrahydrothien-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl Hydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, etc. The terms "cycloalkylene" and "heterocycloalkylene" are not limited to: , refer to the divalent derivatives of cycloalkyl and heterocycloalkyl, respectively.

[0109] Unsaturated hydrocarbons have one or more double or triple bonds. Examples include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadiene) enyl), 2,4-pentadienyl, 3-(l,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl and higher homologs and isomers. Alkyl groups that are limited to hydrocarbon groups are called "homoalkyl" .

[0110] More specifically, as used herein, the term "alkenyl" refers to an alkyl group having at least one carbon atom. C with carbon-carbon double bond 2-20 One hydrogen atom from a straight-chain or branched hydrocarbon moiety within It refers to a monovalent group obtained by removing a molecule. Examples of alkenyl groups include: ethenyl (i.e., vinyl), propenyl, butenyl, 1-methyl-2-butene-1- Examples include yl, pentenyl, hexenyl, octenyl, allenyl and butadienyl.

[0111] As used herein, the term "cycloalkenyl" refers to a group consisting of at least one carbon-carbon It refers to a cyclic hydrocarbon containing a double bond. Examples of cycloalkenyl groups include cyclopropenyl and cyclopropenyl. Cyclobutenyl, cyclopentenyl, cyclopentadiene, cyclohexenyl, 1, 3-Cyclohexadiene, cycloheptenyl, cycloheptatrienyl and cyclooctene Nil is an example.

[0112] As used herein, the term "alkynyl" refers to an alkynyl group having at least one carbon-carbon triple bond. Straight or branched chain C 2-20 Derived from hydrocarbons Examples of "alkynyl" include ethynyl, 2-propynyl (propargyl) and ), 1-propynyl, pentynyl, hexynyl and heptynyl groups.

[0113] The term "alkylene," by itself or as part of another substituent, refers to an alkyl group having 1 to about 20 carbon atoms. Atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, Straight chain derived from alkyl groups having 15, 16, 17, 18, 19 or 20 carbon atoms or branched divalent aliphatic hydrocarbon group. The alkylene group may be linear, branched, or cyclic. The alkylene group may also be optionally unsaturated and / or have one or more Along the alkylene group, it may be substituted with multiple "alkyl group substituents." and one or more oxygen, sulfur, or substituted or unsubstituted nitrogen atoms (referred to herein as "aromatics"). The nitrogen substituents are as described above. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (-(CH2)3-); cyclohexylene (-C6 H 10 -);-CH=CH-CH=CH-;-CH=CH-CH2-;-CH2CH2C H2CH2-, -CH2CH=CHCH2-, -CH2CsCCH2-, -CH2CH2 CH(CH2CH2CH3)CH2-, -(CH2) q -N(R)-(CH2) r -(formula wherein q and r each independently represent an integer of 0 to about 20, for example, 0, 1, 2, 3, , 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, where R is hydrogen or lower alkyl; methylenedioxyl (-O -CH2-O-); and ethylenedioxyl (-O-(CH2)2-O-). The alkylene group can have about 2 to about 3 carbon atoms and can further have 6 to 20 carbon atoms. Generally, an alkyl (or alkylene) group can have 1 to 24 carbon atoms. and groups having 10 or fewer carbon atoms are preferred in some embodiments of the present disclosure. A "lower alkyl" or "lower alkylene" refers to a shorter chain alkyl or alkylene. It is a hydroxyl group, generally having up to 8 carbon atoms.

[0114] The term "heteroalkylene" by itself or as part of another substituent means heteroalkylene. Divalent groups derived from alkyl, such as -CH2-CH2-S-CH2-CH2- and - Groups exemplified by, but not limited to, CH2-S-CH2-CH2-NH-CH2- In the case of heteroalkylene groups, heteroatoms may occupy one or both of the chain termini. (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, a Furthermore, in the case of alkylene and heteroalkylene linking groups, the linking group The orientation of the linking group is not implied by the direction in which the formula is written. For example, the formula - C(O)OR'- represents both -C(O)OR'- and -R'OC(O)-.

[0115] The term "aryl" refers to a single ring or rings fused together, unless otherwise specified. It refers to an aromatic hydrocarbon substituent which may be multiple rings (e.g., 1 to 3 rings) that are covalently linked. The term "heteroaryl" refers to N, O, and S (nitrogen and sulfur atoms are optional). wherein the nitrogen atom(s) are optionally quaternized. an aryl group containing 1 to 4 heteroatoms (in separate rings in the case of multiple rings) A heteroaryl group is an aryl group that is attached to the rest of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, ... phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2 -oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3- Thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1- Isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinoxalinyl Each of the above aryl and heteroaryl ring systems includes aryl and 6-quinolyl. Substituents for "arylene" are selected from the group of acceptable substituents described below. The terms "heteroarylene" and "heteroarylene" refer to the divalent groups of aryl and heteroaryl, respectively. Refers to the form.

[0116] For brevity, the term "aryl" may be used interchangeably with other terms such as aryloxy, When used in combination with arylthiol, arylthiol, arylalkyl, Thus, "arylalkyl" includes both aryl and heteroaryl rings. and the term "heteroarylalkyl" refers to an aryl or heteroaryl group that is Groups attached to alkyl groups (e.g., benzyl, phenethyl, pyridylmethyl, furylmethyl) It means that the carbon atom (e.g., methylene group) is replaced with, for example, an oxygen atom. Groups attached to substituted alkyl groups (e.g., phenoxymethyl, 2-pyridyloxy) However, as used herein, As used herein, the term "haloaryl" refers to an aryl substituted with one or more halogens. means to include only

[0117] When the heteroalkyl, heterocycloalkyl, or heteroaryl has a specific number of members (e.g., When including "3- to 7-membered"), the term "membered" refers to a carbon or heteroatom.

[0118] Additionally, as used herein, the formula [ka] The structure generally represented by the formula: refers to a ring structure, for example, but not limited to, a ring structure having 3 carbon atoms, a ring structure having 4 carbon atoms, , saturated ring structures, partially saturated ring structures and unsaturated ring structures having 5 carbon atoms, 6 carbon atoms, 7 carbon atoms, etc. aliphatic and / or aromatic cyclic compounds containing substituent R groups (wherein R groups are not present); When present, one or more R groups may each be present in the ring. R is a ring structure containing a substituted aryl group (which may be substituted on one or more available carbon atoms of the structure). The presence or absence of R groups and the number of R groups is determined by the value of the variable "n", which generally ranges from 0 to substituted Each R group, if present, is an integer with a value up to the number of carbon atoms in the ring. For example, in the above structure where n is 0 to 2, teeth, [ka] and the like.

[0119] A dashed line representing a bond in a cyclic structure indicates whether the bond is present within the ring or not. That is, a dashed line representing a bond in a cyclic structure indicates that the cyclic structure is It indicates that the ring structure is selected from the group consisting of a saturated ring structure, a partially saturated ring structure, and an unsaturated ring structure.

[0120] JPEG2026009899000027.jpg732 shows the point of attachment of a site to the rest of the molecule.

[0121] When a named atom of an aromatic or heteroaromatic ring is defined as "absent," it is The named atom in is replaced with a direct bond.

[0122] Each of the above terms (e.g., "alkyl," "heteroalkyl," "cycloalkyl," and "Heterocycloalkyl", "aryl", "heteroaryl", "phosphonate" and "Sulfonates" and their divalent derivatives) refer to substituted and unsubstituted forms of the indicated radical. and Optional substituents for each type of radical are provided below.

[0123] Monovalent and divalent derivatives of alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl Conductive groups (alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, Cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl Substituents for the alkyl group (including the group often referred to as -OR', =O, =NR', =N- OR´, -NR´R´´, -SR´, -halogen, -SiR´R´´R´´´, -OC( O)R´, -C(O)R´, -CO2R´, -C(O)NR´R´´, -OC(O)NR ´R´´, -NR´´C(O)R´, -NR´-C(O)NR´´R´´´, -NR´´ C(O)OR´, -NR-C(NR´R´´)=NR´´´, -S(O)R´, -S(O )2R´, -S(O)2NR´R´´, -NRSO2R´, -CN, CF3, fluorinated C 1-4 From alkyl and -NO2, a number from 0 to (2m' + l) (m' is the number of such groups or one of a variety of groups selected from, but not limited to, the total number of carbon atoms in R', R'', R''', and R'''' are each independently hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., 1 to 3 alkyl groups) substituted aryl, substituted or unsubstituted alkyl, alkoxy or may refer to a thioalkoxy group or an arylalkyl group. An "alkoxy" group is an alkyl attached to the rest of the molecule through a divalent oxygen. For example, when a compound of the present disclosure includes multiple R groups, each R group is independently selected and each R' The same applies to R", R'", and R'"' groups when a plurality of these groups are present. When R' and R'' are bonded to the same nitrogen atom, they are bonded to the nitrogen atom in a 4, 5 For example, -NR'R' can form a 6- or 7-membered ring. and 4-morpholinyl. From the above discussion, those skilled in the art will appreciate that the term "alkyl" can also refer to haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)C Groups containing carbon atoms bonded to groups other than hydrogen groups, such as -F3, -C(O)CH2OCH3, etc. It will be understood that this means including

[0124] Similar to the substituents described above for the alkyl group, aryl and heteroaryl groups Exemplary substituents for (and their divalent derivatives) are varied, for example, halogen, -OR´, -NR´R´´, -SR´, -SiR´R´´R´´´, -OC(O)R´, -C(O)R´, -CO2R´, -C(O)NR´R´´, -OC(O)NR´R´´, -NR´´C(O)R´, -NR´-C(O)NR´´R´´´, -NR´´C(O)O R´, -NR-C(NR´R´´R´´´)=NR´´´´, -NR-C(NR´R´´ )=NR´´´, -S(O)R´, -S(O)2R´, -S(O)2NR´R´´, -N RSO2R', -CN and -NO2, -R', -N3, -CH(Ph)2, fluoro(C 1-4 ) Alkoxo and Fluoro (C 1-4 ) alkyl to an open aromatic ring system up to the total number of valences of the atoms in the are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroaryl, alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; For example, when a compound of the present disclosure includes multiple R groups, each R group may be independently selected to The same applies to each R', R'', R''', and R'''' groups when multiple of these groups are present. be.

[0125] Two of the substituents on adjacent atoms of an aryl or heteroaryl ring are optionally In the formula -TC(O)-(CRR´) q may form a ring of -U-, where T and U are , each independently represents -NR-, -O-, -CRR'- or a single bond, and q is 0 to 3. Alternatively, the number of substituents on adjacent atoms of an aryl or heteroaryl ring is an integer. Two of these are optionally of the formula -A-(CH2) r may be substituted with a -B- substituent wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O) -, -S(O)2-, -S(O)2NR'- or a single bond, and r is an integer of 1 to 4. .

[0126] One of the single bonds in the new ring thus formed is optionally replaced with a double bond. Alternatively, the substituents on adjacent atoms of the aryl or heteroaryl ring may be Two of them are optional and have the formula -(CRR´) s -X´-(C´´R´´´) d -Replacement group, wherein s and d are independently an integer of 0 to 3, and X' is , -O-, -NR´-, -S-, -S(O)-, -S(O)2- or -S(O)2NR´ The substituents R, R', R" and R"' are independently hydrogen, substituted or unsubstituted. alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl; It may be selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

[0127] As used herein, the term "acyl" refers to a group in which the -OH of the carboxyl group is substituted with another substituent. and has the general formula RC(=O)-, where R is as defined herein. alkyl, alkenyl, alkynyl, aryl, carboxyl, heterocyclic, etc. (aromatic heterocyclic group or an aromatic heterocyclic group). Thus, the term "acyl" specifically includes 2- Aryl acyl groups such as (furan-2-yl)acetyl- and 2-phenylacetyl groups Specific examples of acyl groups include acetyl and benzoyl. The groups include amide, -RC(=O)NR', ​​ester, -RC(=O)OR', ketone, -R Also intended to include C(=O)R' and the aldehyde, -RC(=O)H.

[0128] The terms "alkoxyl" or "alkoxy" are used interchangeably herein and refer to an oxygen atom. A saturated (i.e., alkyl-O-) group or an unsaturated ( i.e., alkenyl-O- and alkynyl-O- groups, where the term "alkyl" refers to "," "alkenyl" and "alkynyl" are as defined above, and examples thereof include methoxyl, ethoxyl, and the like. n-Butoxyl, propoxyl, isopropoxyl, n-butoxyl, sec-butoxyl, te Includes rt-butoxyl, n-pentoxyl, neopentoxyl, n-hexoxyl, etc. , C 1-20 Contains linear, branched or cyclic saturated or unsaturated oxo-hydrocarbon chains within It is possible.

[0129] As used herein, the term "alkoxyalkyl" refers to an alkyl-O-alkyl group. ethoxymethyl groups, for example, methoxyethyl or ethoxymethyl groups.

[0130] "Aryloxyl" refers to an aryl-O- group in which the aryl group is as previously defined. and aryl groups include substituted aryl. As used herein, the term "aryl" "Hexyloxyl" refers to phenyloxyl or hexyloxyl as well as alkyl, substituted alkyl It may refer to phenyloxyl or hexyloxyl substituted with phenyl, halo or alkoxyl. do.

[0131] "Aralkyl" refers to an aryl-alkyl- group, where the aryl and alkyl are As stated above, aryl and alkyl include substituted aryl and substituted alkyl. Exemplary aralkyl groups include benzyl, phenylethyl, and naphthylmethyl. do.

[0132] "Aralkyloxyl" refers to an aralkyl-O- group, where the aralkyl group is as defined above. An exemplary aralkyloxyl group is benzyloxyl, i.e., CH 5-CH2-O-. The aralkyloxyl group can be optionally substituted.

[0133] "Alkoxycarbonyl" refers to an alkyl-OC(=O)- group. The oxycarbonyl group includes methoxycarbonyl, ethoxycarbonyl, butyloxycarbonyl, Examples include tert-butyloxycarbonyl and tert-butyloxycarbonyl.

[0134] "Aryloxycarbonyl" refers to an aryl-OC(=O)- group. Aryloxycarbonyl groups include phenoxy- and naphthoxy-carbonyl .

[0135] "Aralkoxycarbonyl" refers to an aralkyl-OC(=O)- group. The alkoxycarbonyl group is benzyloxycarbonyl.

[0136] "Carbamoyl" refers to an amide group of the formula -C(=O)NH2. "R" refers to the group R'RN-C(=O)-, where one of R and R' is hydrogen. The other of R and R' is alkyl and / or substituted alkyl as described above. The term "dialkylcarbamoyl" refers to the group R'RN-C(=O)-, where R and R Each of the ' is independently alkyl and / or substituted alkyl as defined above.

[0137] As used herein, the term "carbonyldioxyl" refers to a group of the formula -OC(=O)-O R refers to the carbonate group.

[0138] The term "acyloxyl" refers to an acyl-O- group, where acyl is as previously defined. do.

[0139] The term "amino" refers to the -NH2 group, where one or more hydrogen radicals are replaced by an organic group. Nitrogen-containing ammonium hydroxides, as known in the art, can be obtained from ammonia by For example, the terms "acylamino" and "alkylamino" refer to the groups: Refers to certain N-substituted organic groups having acyl and alkyl substituents.

[0140] As used herein, an "aminoalkyl" refers to an amino group covalently attached to an alkylene linker. More particularly, as used herein, alkylamino, dialkylamino, The terms no and trialkylamino are attached to the parent molecular moiety through a nitrogen atom. The term alkylamino refers to one, two or three alkyl groups as defined above. refers to a group having the structure -NHR', where R' is an alkyl group as defined above. while the term dialkylamino refers to a group having the structure -NR'R', wherein R' and R'' are each independently selected from the group consisting of alkyl groups. Trialkylamino refers to a group having the structure -NR'R'R'', where R', R" and R" are each independently selected from the group consisting of alkyl groups. wherein R', R'' and / or R''' taken together optionally represent -(CH) k -( (k is an integer of 2 to 6). Examples include methylamino, dimethylamino, , ethylamino, diethylamino, diethylaminocarbonyl, methylethylamino, i isopropylamino, piperidino, trimethylamino and propylamino, Not limited to these.

[0141] An amino group is -NR'R', where R' and R' are generally hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted It is selected from aryl or substituted or unsubstituted heteroaryl.

[0142] The terms alkyl thioether and thioalkoxyl are substituted by a sulfur atom to form the parent molecular moiety. Saturated (i.e., alkyl-S-) or unsaturated (i.e., alkenyl) Examples of thioalkoxy moieties include methylthio and alkynyl-S- groups. Examples include thio, ethylthio, propylthio, isopropylthio, and n-butylthio. Not limited to these.

[0143] "Acylamino" refers to an acyl-NH- group, where acyl is as previously described. "Aroylamino" means an aroyl-NH- group in which aroyl is as previously described. do.

[0144] The term "carbonyl" refers to the group -C(=O)- and is represented by the general formula RC(=O)H. It may contain an aldehyde group.

[0145] The term "carboxyl" refers to a -COOH group. Such groups are also referred to herein as "carboxyl groups." It is also called the "bonic acid" moiety.

[0146] The term "cyano" refers to the group --C.ident.N.

[0147] As used herein, the terms "halo," "halide," or "halogen" refer to a full Additionally, terms such as "haloalkyl" refer to molybdenum, chloro, bromo, and iodo groups. For example, the term "halo(C1 -4 ) alkyl" is trifluoromethyl, 2,2,2-trifluoroethyl, 4-chloro It is meant to include, but not limited to, 3-bromobutyl, 3-bromopropyl and the like.

[0148] The term "hydroxyl" refers to an --OH group.

[0149] The term "hydroxyalkyl" refers to an alkyl group substituted with an --OH group.

[0150] The term "mercapto" refers to the group --SH.

[0151] As used herein, the term "oxo" refers to a group that is free from a carbon atom or another element, such as the nitrogen of a pyridine ring. The term "pyridine" refers to an oxygen atom that is double-bonded to a cyclic alkyl group (including alkyl groups) to form pyridine N-oxide.

[0152] The term "nitro" refers to the -NO2 group, -N + (=O)-O - It can also be expressed as:

[0153] The term "thio" refers to a group as defined herein above in which a carbon or oxygen atom has been replaced with a sulfur atom. This refers to a compound that has been synthesized.

[0154] The term "sulfate" refers to the -SO4 group.

[0155] As used herein, the term thiohydroxyl or thiol refers to a group of formula -SH Refers to...

[0156] More specifically, the term "sulfide" refers to a compound having a group of formula -SR.

[0157] The term "sulfone" refers to a compound having a sulfonyl group -S(O2)R'.

[0158] The term "sulfoxide" refers to a compound with a sulfinyl group -S(O)R.

[0159] The term "ureido" refers to a urea group of formula -NH-CO-NH2.

[0160] "S(=O)(=NR 10 )-R 11 " group is described, for example, in Frings et al., Sulfoximines from a Medicinal Chemist´s Perspective: Physicochemistry and in vit ro Parameters Relevant for Drug Discover y, European Journal of Medicinal Chemist ry 126 (2017) 225e245, which is incorporated by reference in its entirety. incorporated herein.

[0161] Throughout this specification and claims, a given chemical formula or name refers to all tautomeric forms. isomers, homologues and optical and stereoisomers as well as mixtures of such isomers exist. Racemic mixtures are intended to be included.

[0162] Certain compounds of the present disclosure may have asymmetric carbon or sulfur atoms (optical or chiral centers). or double bonds (enantiomers, racemates, diastereomers, tautomers, Any isomer may be (R)- or (S)- in terms of absolute stereochemistry, or in the case of amino acids. (stereoisomers which may be defined as D- or L- in some cases), each isomer is within the scope of this disclosure. Some compounds of the present disclosure are too unstable to synthesize and / or isolate. This disclosure does not include racemic, scale-mixtures, or mixtures thereof known in the art. The term "optically active" is intended to include compounds in optically pure form. The (S)- or D- and L-isomers are prepared using chiral synthons or chiral reagents. The compounds described herein may be obtained by olefin-linked or resolved using conventional techniques. If the compound contains other geometrically asymmetric centers, the compound may be E and Z unless otherwise specified. Both geometric isomers are intended to be included.

[0163] Unless otherwise indicated, structures depicted herein represent all stereochemical representations of that structure. The present invention is also intended to include both configurations, i.e., the R and S configurations of each asymmetric center. Mixtures of enantiomers and diastereomers as well as single stereochemical isomers of the compounds of are also within the scope of this disclosure.

[0164] Certain compounds of the present disclosure may exist in tautomeric forms, and all such compounds It will be apparent to one skilled in the art that tautomers of the formula (I) are within the scope of the present disclosure. As used herein, the term "tautomer" refers to a compound that exists in equilibrium and changes from one isomer to another. It refers to one of two or more structural isomers that are readily convertible.

[0165] Unless otherwise indicated, structures depicted herein may be represented by one or more isotopically enriched forms. It is also meant to include compounds that differ only in the presence of an atom, e.g., hydrogen replaced with deuterium or A compound having this structure or carbon substituted with tritium 13 C or 14 C enriched carbon Compounds having this structure with substitutions are within the scope of this disclosure.

[0166] The compounds of the present disclosure may contain naturally occurring hydroxyl groups at one or more of the atoms that constitute such compounds. For example, the compounds may contain uncommon proportions of atomic isotopes, such as deuterium ( 2 H) , tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C) and other The compounds of the present disclosure, whether radioactive or not, may be radiolabeled with a radioisotope. All isotopic variations are encompassed within the scope of the present disclosure.

[0167] The compounds of the present disclosure may exist as salts. The present disclosure includes such salts. Examples of usable salt forms include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, and the like. Acid salts, maleates, acetates, citrates, fumarates, tartrates (e.g., (+)-alcohol (-)-tartrate or mixtures thereof, including racemic mixtures), succinate, benzoate These salts include salts of amino acids such as glutamic acid and acetic acid. It can be prepared by the methods described in the literature. It can also be prepared by sodium salts, potassium salts, calcium salts, base addition salts such as ammonium salts, organic amino salts, or magnesium salts or similar Salts are also included. When compounds of the present disclosure contain relatively basic functional groups, such compounds is reacted with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. The acid addition salts can be obtained by contacting with or by ion exchange. Examples of suitable acid addition salts include those of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogen carbonate, phosphoric acid, and phosphate. Salts derived from inorganic acids such as monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, monohydrogen sulfate, hydroiodic acid, or phosphoric acid and acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, Vinyl acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolyls Examples of the salts include salts derived from organic acids such as sulfonic acid, citric acid, tartaric acid, and methanesulfonic acid. Also included are salts of amino acids such as ginate and salts of organic acids such as glucuronic acid or galacturonic acid. Certain compounds of the present disclosure can be converted into either a base or acid addition salt. The compound contains both basic and acidic functional groups that allow it to be reacted with other compounds.

[0168] The neutral forms of the compounds can be prepared by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound can be regenerated by changing its properties, such as solubility in polar solvents. The various salt forms differ in certain physical properties.

[0169] Certain compounds of the present disclosure exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to the unsolvated forms and are within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. Generally, all physical forms are equivalent for the uses contemplated by this disclosure. are intended to be within the scope of the disclosure.

[0170] In addition to salt forms, the present disclosure provides compounds that are in prodrug form. Prodrugs of the compounds described above readily undergo chemical changes under physiological conditions to form the compounds of the present disclosure. Furthermore, prodrugs can be synthesized chemically or biologically in an ex vivo environment. The compounds of the present disclosure can be converted by chemical methods. For example, prodrugs can be prepared by the appropriate When placed in a transdermal patch reservoir along with an appropriate enzyme or chemical reagent, the compounds of the present disclosure slowly react with the can be transformed into things.

[0171] The term "protecting group" refers to a group that protects some or all of the reactive sites in a compound and that Chemical moieties that prevent such moieties from participating in chemical reactions until removed, e.g., T W. Greene, PGM Wuts, Protective Gro ups in Organic Synthesis, 3rd ed. John W. Refers to the sites listed and described in Iley & Sons (1999). When protecting groups are used, it is advantageous that each (different) protecting group be removable by a different means. Such protecting groups can be distinguished by protecting groups that are cleaved under very different reaction conditions. For example, protecting groups can be removed by acid, base, and hydrogenolysis. Trityl, dimethoxytrityl, acetal and tert-butyldimethyl Groups such as methylsilyl are acid reactive and their use in the isolation of carboxy reactive sites and hydroxyl groups. Protection of the hydroxy-reactive sites is achieved by hydrogenolysis-removable Cbz groups and base-labile Fmoc groups. The reaction can be carried out in the presence of an amino group protected with a carboxylic acid and hydroxyl reactive group. Protection of the moiety with base-labile groups such as, but not limited to, methyl, ethyl, and acetyl, provides a carbamate. Acid-reactive groups such as tert-butyl carboxylate or those that are stable to both acid and base but not hydrolytically removable This can be carried out in the presence of a removable carbamate protected amine.

[0172] Carboxylic acid and hydroxy reactive sites are protected by hydrolytically removable protecting groups such as benzyl groups. Amine groups capable of hydrogen bonding with acids can be protected with base-reactive groups such as Fmoc. Carboxylic acid reactive sites can be protected with an acid such as 2,4-dimethoxybenzyl. The amino groups can be protected with fluoride-removable protecting groups, and the coexisting amino groups are reactive to fluoride. It can be protected with a silyl carbamate.

[0173] Allyl blocking groups are useful when acid and base protecting groups are present because , because the former is stable and can be subsequently removed by metal or π-acid catalysts. For example, an allyl-protected carboxylic acid can be reacted with an acid-reactive t-butyl carbamate or base. In the presence of a reactive acetate amine protecting group, the palladium(O)-catalyzed deprotection Yet another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group is protected and cannot react. Once released from the resin, the functional group becomes available to react.

[0174] Representative blocking / protecting groups include the following moieties: [ka] These include, but are not limited to:

[0175] Following long-standing patent law practice, the terms "a" and "an" and "the" ) means "one or more" as used in this application, including the claims. Thus, for example, a reference to a "subject" is inappropriate for the context to the contrary (e.g., a plurality of subjects). ) includes multiple subjects, except when it is clear that

[0176] Throughout this specification and claims, the term "comprises" "Including" and "comprising" may have other meanings in the context. Unless otherwise specified, the terms "include" and "includes" are used in a non-exclusive sense. " and grammatical variations thereof are intended to be non-limiting and do not affect the enumeration of items in a list. This does not exclude other similar items that may be substituted for or added to the listed items.

[0177] For purposes of this specification and the appended claims, unless otherwise indicated, and amounts, sizes, dimensions, proportions, shapes, compositions, parameters, All numbers expressing percentages, amounts, properties, and other numerical values ​​are expressly defined as values, In all cases, the term "about" shall be used, even if not expressly appearing in conjunction with a quantity or range. Therefore, unless expressly stated to the contrary, The numerical parameters set forth in the following specification and attached claims are not precise and should not be construed as limiting the scope of the invention. It is not necessary to be tight, but the tolerances, etc. may vary depending on the desired properties sought to be obtained by the subject matter of the present disclosure. Approximations may be made to reflect conversion factors, rounding, measurement error, etc., and other factors known to those skilled in the art. and / or may be larger or smaller as appropriate. For example, the term "about" The term, when referring to a value, may refer to a range from the specified amount, in some embodiments ±100%, in other embodiments ±100%. In some embodiments, ±50%, in some embodiments, ±20%, in some embodiments, is ±10%, in some embodiments ±5%, in some embodiments ±1%, in some embodiments ±1% In some embodiments, the variation is ±0.5%, and in some embodiments, ±0.1%. It may be meant that such variations are not inconsistent with the principles of practicing the disclosed methods or the disclosed methods. This is because it is appropriate for utilizing the composition.

[0178] Additionally, the term "about" when used in connection with one or more numerical values ​​or ranges of values. When a range is used, it should be understood to refer to all such values, including all values ​​within the range, and Modify the range by extending the upper and lower limits of the listed numeric values. A range enumeration includes all numbers included within the range, e.g., all integers including their fractions ( For example, a list of 1 to 5 includes 1, 2, 3, 4, and 5 as well as fractions thereof, e.g., 1.5 , 2.25, 3.75, 4.1, etc.) and any range therein. [Example]

[0179] The following examples provide guidance to those of skill in the art for practicing representative embodiments of the presently disclosed subject matter. It is included for the sole purpose of providing information that would be readily apparent to one skilled in the art in light of this disclosure and the general level of skill of one of ordinary skill in the art. If anything, the following examples are intended to be merely illustrative and not to be taken as limiting the scope of the subject matter of this disclosure. It will be appreciated that many changes, modifications and variations may be made without departing from the scope of the present invention. The synthetic descriptions and specific examples that follow are for illustrative purposes only and are not intended to be limiting unless otherwise specified. It should not be construed as limiting the preparation of the disclosed compounds in any way.

[0180] (Synthetic Procedure) Exemplary compounds were prepared via several general synthetic routes described in the Examples below. Any of the compounds of the present disclosure may be prepared by one of these synthetic routes or specific examples. or can be prepared according to several methods or through modifications thereof available to those skilled in the art.

[0181] (Intermediate 1; 2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl) (ethyl)pyridine-3-carboxylic acid) [Method A] [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3-carboxamide in MeCN (5 mL) carboxylic acid (500 mg, 2.22 mmol), 4-fluoro-2-methoxyphenol (2 78 μL, 2.44 mmol) and cesium carbonate (1806 mg, 5.54 mmol) The mixture was stirred at 80° C. for 18 hours. After cooling, the contents were diluted with 20 mL of water and The mixture was acidified to pH 5 with careful addition of HCl and stirred for 2 hours. The precipitate was collected by filtration. Washed with water, dried under vacuum, 2-(4-fluoro-2-methoxy-phenoxy)-5-( (trifluoromethyl)pyridine-3-carboxylic acid was obtained as a beige solid (695 mg, 2.10 mmol, yield 94.6%). MS, ES+ m / z 332.0 [ M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 13.74 (br. s ., 1 H), 8.67 (br. s., 1 H), 8.50 (s, 1 H), 7.22 (dd, J=8.97, 5.68 Hz, 1 H), 7.1 0 (dd, J=11.12, 2.78 Hz, 1 H), 6.79 - 6. 86 (m, 1 H), 3.70 (s, 3 H).

[0182] (Intermediate 2: 2-(benzotriazol-1-yloxy)-N-(3-methylsulfonyl) (phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide [Method B] [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3 in chloroform (10 mL) -carboxylic acid (508 mg, 2.25 mmol), 3-methylsulfonylaniline (42 4 mg, 2.48 mmol), HBTU (854 mg, 2.25 mmol) and DIPE A (981 μL, 5.63 mmol) was stirred at room temperature for 40 hours. mol) was added to chloroform (10 mL) and stirred at room temperature for 40 hours. The residue was treated with water / MeOH (5:1). After washing, the mixture was stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, and Dry in vacuo and 2-(benzotriazol-1-yloxy)-N-(3-methylsulfonyl) (5-(trifluoromethyl)pyridine-3-carboxamide) in beige The compound was obtained as a colored solid (665 mg, 1.39 mmol, 61.9% yield). MS, ES + m / z 448.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.37 (s, 1 H), 8.88 (d, J=2.27 Hz, 1 H), 8.72 (d, J =1.01 Hz, 1 H), 8.43 (s, 1 H), 8.20 (d, J=8.59 Hz, 1 H), 8.03 - 8.07 (m, 1 H), 7 .83 (d, J=8.59 Hz, 1 H), 7.67 - 7.77 (m, 3 H), 7.54 - 7.58 (m, 1 H), 3.25 (s, 3 H).

[0183] (Intermediate 3: 6-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3 -methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0184] Step 1: 2,6-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxylate Synthesis of ruboxamide [Method C] [ka] 2,6-Dichloropyridine-3-carbonyl chloride (20 mL) in chloroform (5 mL) 0mg, 0.950mmol), 3-methylsulfonylaniline (179mg, 1.05 A mixture of 1000 mmol) and DIPEA (414 μL, 2.38 mmol) was stirred at room temperature for 24 hours. The contents were treated with 10% Na2CO3, extracted with CHCl3 (3x), and the solvent was removed in vacuo to give 2,6-dichloro-N-(3-methylsulfonylphenyl)pyridine- The 3-carboxamide was obtained as a yellow foam (378 mg, 1.10 mmol, 11% yield). 5%), which was used without further purification. MS, ES+ m / z 344.9 [M+H]+.

[0185] Step 2: 6-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3- Synthesis of methylsulfonylphenyl)pyridine-3-carboxamide [Method D] [ka] Crude 2,6-dichloro-N-(3-methylsulfonylphenyl)- (I)pyridine-3-carboxamide (276 mg, 0.800 mmol), 4-fluoro -2-Methoxyphenol (91.1 μL, 0.800 mmol) and cesium carbonate (2 The mixture of 20 ml of 2,000 mg of 2,000 sucrose (73 mg, 0.840 mmol) was stirred at room temperature for 23 hours. The mixture was diluted with 1 L of water and stirred at room temperature for 2 h. The resulting precipitate was collected by filtration and washed with water. , dried in vacuo, and 6-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N- (3-Methylsulfonylphenyl)pyridine-3-carboxamide (242 mg, 0.5 36 mmol, 67.0% yield) was obtained as a white solid. MS, ES+ m / z 45 1.1 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1 H), 8.41 (s, 1 H), 8.19 (d, J=7.83 Hz, 1 H), 7.96 (d, J=7.58 Hz, 1 H), 7.63 - 7. 71 (m, 2 H), 7.32 - 7.39 (m, 2 H), 7.12 (dd, J=10.74, 2.91 Hz, 1 H), 6.86 (td, J =8.46, 2.78 Hz, 1 H), 3.73 (s, 3 H), 3.2 2 (s, 3 H)

[0186] (Intermediate 4; 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethylphenyl)- Methyl)pyridine-3-carboxamide [Method E] [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3- in chloroform (5 mL) Carbonyl chloride (250 mg, 1.02 mmol), 3-methylsulfonylaniline (193 mg, 1.13 mmol) and DIPEA (446 μL, 2.56 mmol) The mixture was stirred at room temperature for 24 hours. The contents were treated with 10% Na2CO3 and CHCl3( 3x) ​​and the solvent removed in vacuo to give a yellow foam which was diluted with MeOH / 2% NaCl The solid was collected by filtration, washed with water, and dried in vacuo. Dry and 2-chloro-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl) (I)pyridine-3-carboxamide (175 mg, 0.462 mmol, 45.1% yield) ) was obtained as a beige solid. MS, ES+ m / z 379.0 [M+H]+ 1H-NMR (400 MHz, DMSO-d6) δ 11.17 (s, 1 H), 9.04 (s, 1 H), 8.72 (d, J=2.27 Hz , 1 H), 8.35 (s, 1 H), 7.94 (d, J=7.83 H z, 1 H), 7.67 - 7.76 (m, 2 H), 3.25 (s, 3 H).

[0187] (Example 1: N-(1,3-benzothiazol-6-yl)-2-(4-fluoro-2- Methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide [Method F] [ka] 2-(4-fluoro-2-methoxy-phenoxy)-5- in chloroform (2 mL) (Trifluoromethyl)pyridine-3-carboxylic acid (Intermediate 1) (30.0 mg, 0.0 90 mmol), 1,3-benzothiazol-6-amine (15.0 mg, 0.100 m mol), HBTU (37.8 mg, 0.100 mmol) and DIPEA (29.3 m g, 39.4 μL, 0.230 mmol) was stirred at room temperature for 20 hours. The mixture was removed under a stream of N2 and the residue was treated with water / MeOH (3:1). After ultrasonic treatment, the mixture was stirred at room temperature for 3 hours. The resulting precipitate was collected by filtration and diluted with water. Washed and dried in vacuo, N-(1,3-benzothiazol-6-yl)-2-(4-fluorophenyl)- (2-Methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carbo The oxamide (35.4 mg, 0.0764 mmol, 84.3% yield) was obtained as a beige solid MS, ES+ m / z 464.0 [M+H]+. 1H-NMR ( 400 MHz, DMSO-d6) δ 10.88 (s, 1 H), 9.32 (s, 1 H), 8.70 (d, J=2.02 Hz, 1 H), 8.6 6 - 8.68 (m, 1 H), 8.53 (d, J=2.53 Hz, 1 H), 8.09 (d, J=8.84 Hz, 1 H), 7.75 (dd, J=8.84, 2.02 Hz, 1 H), 7.35 (dd, J=8.84 , 5.81 Hz, 1 H), 7.11 (dd, J=10.74, 2.91 Hz, 1 H), 6.85 (td, J=8.53, 2.91 Hz, 1 H), 3.72 (s, 3 H).

[0188] The following compounds were synthesized according to Method F: [ka] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7]

[0189] Example 21: 2-(2,4-dichlorophenoxy)-N-(3-methylsulfonylphenoxy)- (Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide [Method G] [ka] 2-(benzotriazol-1-yloxy)-N-(3-methyl ... (Cysulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (Intermediate 2) (50.0 mg, 0.100 mmol), 2,4-dichlorophenol (2 0.5 mg, 0.130 mmol) and cesium carbonate (102 mg, 0.310 mmol) The mixture was stirred at 50°C for 1 hour. The solvent was removed under a stream of N2, and the residue was dissolved in water / Me The mixture was briefly sonicated and then stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 2-(2,4-dichloro-2-methyl-2-propanol). (chlorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl ) pyridine-3-carboxamide (43.6 mg, 0.0863 mmol, yield 82.4 %) as an off-white solid. MS, ES+ m / z 505.0 [M +H]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.07 (s, 1 H), 8.71 - 8.73 (m, 1 H), 8.63 (d, J=2.5 3 Hz, 1 H), 8.39 - 8.42 (m, 1 H), 7.97 - 8.01 (m, 1 H), 7.82 - 7.84 (m, 1 H), 7. 66 - 7.74 (m, 2H), 7.53 - 7.60 (m, 2H) , 3.24 (s, 3 H).

[0190] The following compounds were synthesized according to Method G: [ka] [Table 2-1] [Table 2-2] [Table 2-3]

[0191] The following compounds were synthesized according to Method G: [ka] [Table 3-1] [Table 3-2] [Table 3-3]

[0192] Example 33: 2-(2,6-dimethylphenoxy)-N-(3-methylsulfonylphenoxy)- (Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide [Method H] [ka] 2-Chloro-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (Intermediate 4) (59 mg, 0.16 0 mmol), 2,6-dimethylphenol (20.9 mg, 0.170 mmol) and The mixture was stirred at room temperature for 18 hours. The contents were diluted with EtOAc and washed with water (3x), brine (1x), and concentrated with MgSO4. Drying, filtration and removal of the solvent in vacuo gave a residue which was purified by automated normal phase chromatography. (0-100% EtOAc / heptane, 4 g silica gel cartridge) and purified 2-( 2,6-dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl) (fluoromethyl)pyridine-3-carboxamide (32.6 mg, 0.0702 mmol, (45.1% yield) was obtained as a white foam. MS, ES+ m / z 465.0 [M +H]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.64 (dd, J=2.53, 1.01 Hz, 1 H), 8.5 9 (d, J=2.53 Hz, 1 H), 8.42 - 8.44 (m, 1 H), 7.98 (dt, J=7.58, 1.89 Hz, 1 H), 7. 66 - 7.73 (m, 2H), 7.08 - 7.16 (m, 3H) , 3.23 (s, 3 H), 2.07 (s, 6 H).

[0193] The following compounds were synthesized according to Method H: [ka] [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7]

[0194] The following compounds were synthesized according to Method H: [ka] [Table 5-1] [Table 5-2]

[0195] The following compounds were synthesized according to Method H: [ka] [Table 6-1] [Table 6-2]

[0196] Example 66: 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonyl) (sulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide [ka]

[0197] Step 1: 2-chloro-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl) Synthesis of ethylpyridine-3-carboxamide [ka] HBTU (185 mg, 0.490 mmol), DIPEA in chloroform (5 mL) (170 μL, 0.980 mmol), 2-chloro-6-(trifluoromethyl)pyridin aniline-3-carboxylic acid (100 mg, 0.440 mmol) and 3-methylsulfonylaniline The mixture was stirred at room temperature for 4 days (for convenience). The contents were treated with 5% Na2CO3 and extracted with CHCl3 (3x). The organic extracts were The mixture was combined and the solvent removed in vacuo to give a residue which was purified by automated normal phase chromatography (0-10 0% EtOAc / heptane, 12 g silica gel cartridge) to obtain 2-chloro-N -(3-Methylsulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carbohydrate Voxamide (86.2 mg, 0.229 mmol, 51.3% yield) was obtained as a yellow solid. Ta. MS, ES+ m / z 379.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1 H), 8.48 (d, J=7.83 Hz, 1 H), 8.37 (t, J =1.77 Hz, 1 H), 8.17 (d, J=7.58 Hz, 1 H) , 7.92 (dt, J=7.71, 1.83 Hz, 1 H), 7.72 - 7.76 (m, 1 H), 7.67 - 7.72 (m, 1 H), 3 .25 (s, 3 H).

[0198] Step 2: 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfo) Synthesis of (6-(trifluoromethyl)phenyl)pyridine-3-carboxamide [ka] 2-Chloro-N-(3-methylsulfonylphenyl)-6-(trimethylphenyl)-2-chloro ... (trifluoromethyl)pyridine-3-carboxamide (40.0 mg, 0.110 mmol ), 4-fluoro-2-methoxyphenol (15.1 μL, 0.130 mmol) and A mixture of cesium carbonate (103 mg, 0.320 mmol) was heated at 80°C for 1 hour, and then The mixture was stirred at room temperature overnight, and the contents were diluted with EtOAc and washed with water (3x) and brine (1x). The residue was washed, dried over MgSO4, filtered, and the solvent removed in vacuo to give a residue which was then purified by automated normal phase chromatography. Chromatography (0-100% EtOAc / heptane, 4 g silica gel cartridge) ) and purified by 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonyl)propanol. (phenylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (46. 5 mg, 0.0960 mmol, 90.9% yield) as a yellow solid. MS, ES + m / z 485.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.02 (s, 1 H), 8.42 (s, 1 H), 8.37 (d, J=7.33 Hz, 1 H), 7.96 (d, J=7.58 Hz, 1 H), 7.75 (d, J=7.58 Hz, 1 H), 7.65 - 7.73 (m, 2 H), 7 .33 (dd, J=8.72, 5.94 Hz, 1 H), 7.12 (dd , J=10.61, 2.78 Hz, 1 H), 6.85 (td, J=8. 46, 2.78 Hz, 1 H), 3.69 (s, 3 H), 3.23 ( s, 3 H).

[0199] Example 67: 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonyl) (sulfonylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (Method I) [ka]

[0200] Step 1: 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl) Synthesis of ethyl pyridine-3-carboxylate [ka] 4-Chloro-6-(trifluoromethyl)pyridine-3-carbohydrate in MeCN (3 mL) Ethyl hydroxylate (150 mg, 0.668 mmol), 4-fluoro-2-methoxyphenyl ethanol (95.1 μL, 0.834 mmol) and cesium carbonate (653 mg, 2.00 The mixture of 100 mmol) was stirred at room temperature for 1 hour. The contents were treated with water and stirred at room temperature for 3 days. The precipitate was collected by filtration, washed with water, dried in vacuo, and purified by filtration to give 4-(4-fluoro-2-methyl-2-propanol). -2-Methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid Ethyl (186 mg, 0.518 mmol, 77.5% yield) was obtained as an off-white solid. MS, ES+ m / z 360.0 [M+H]+. 1H-NMR (4 00 MHz, DMSO-d6) δ 9.03 (s, 1 H), 7.35 ( dd, J=8.84, 5.81 Hz, 1 H), 7.23 (dd, J=1 0.61, 3.03 Hz, 1 H), 6.88 - 6.95 (m, 2 H ), 4.37 (q, J=7.07 Hz, 2 H), 3.76 (s, 3 H), 1.33 (t, J=7.07 Hz, 3 H).

[0201] Step 2: 4-(4-fluoro-2-methoxy-phenoxy)-6-(trifluoromethyl) Synthesis of pyridine-3-carboxylic acid [ka] 4-(4-fluoro-2-methoxy-phenoxy)-2-methyl-2-propanol in THF (2 mL) and water (0.1 mL) Ethyl 6-(trifluoromethyl)pyridine-3-carboxylate (182 mg, 0 0.507 mmol) and lithium hydroxide monohydrate (23.4 mg, 0.558 mmol) The mixture was stirred at room temperature for 7 days (for convenience). The solvent was removed under a stream of N2 and the contents were rehydrated with water. (15 mL). 6N HCl was carefully added to lower the pH to pH 5. 3 hours After stirring, the precipitate was collected by filtration, washed with water, dried in vacuo, and purified to give 4-(4-fluoro- 2-Methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxylic acid ( The compound (102.6 mg, 0.3098 mmol, 61.1% yield) was obtained as a white solid. , ES+ m / z 332.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 13.83 (br. s ., 1 H), 9.00 (s, 1 H), 7.35 (dd, J=8.72 , 5.68 Hz, 1 H), 7.23 (dd, J=10.74, 2.65 Hz, 1 H), 6.92 (td, J=8.46, 3.03 Hz, 1 H), 6.86 (s, 1 H), 3.76 (s, 3 H).

[0202] Step 3: 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfo) Synthesis of (6-(trifluoromethyl)phenyl)pyridine-3-carboxamide [ka] 4-(4-fluoro-2-methoxy-phenoxy)-6-( (trifluoromethyl)pyridine-3-carboxylic acid (46.0 mg, 0.139 mmol) , 3-methylsulfonylaniline (26.2 mg, 0.153 mmol), HBTU (5 7.9 mg, 0.153 mmol) and DIPEA (60.5 μL, 0.347 mmol) The mixture was stirred at room temperature for 18 hours. The solvent was removed under a stream of N2 and the residue was dissolved in water / Me The mixture was briefly sonicated and then stirred at room temperature for 24 hours. The resulting precipitate was collected by filtration, washed with water, dried in vacuo, and purified by filtration to give 4-(4-fluoro- -2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)-6-(trifluoromethyl)- (fluoromethyl)pyridine-3-carboxamide (55.0 mg, 0.114 mmol, yield The compound was obtained as a white solid (yield 81.7%). MS, ES+ m / z 485.0 [M+H ]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.08 (s , 1 H), 8.93 (s, 1 H), 8.41 (s, 1 H), 7. 95 (d, J=7.33 Hz, 1 H), 7.65 - 7.73 (m, 2 H), 7.42 (dd, J=8.84, 5.81 Hz, 1 H), 7 .22 (dd, J=10.61, 2.78 Hz, 1 H), 6.96 (s , 1 H), 6.92 (td, J=8.46, 2.78 Hz, 1 H), 3.77 (s, 3 H), 3.23 (s, 3 H).

[0203] The following compounds were synthesized according to Method I: [ka] [Table 7-1] [Table 7-2]

[0204] Example 73: 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[ 2-(Dimethylamino)-4-pyridyl]-6-(trifluoromethyl)pyridine-3- Carboxamide) [Method J] [ka]

[0205] Step 1: Synthesis of 4-chloro-6-(trifluoromethyl)pyridine-3-carbaldehyde Growth [ka] 4-Chloro-2-(trifluoromethyl)pyridine (24.7 g, To a stirred solution of LiHMDS (149.66 mL, 1 The solution was stirred at -78°C for 2 hours, and then 0 The solution was stirred at -78°C for 10 minutes. After cooling the solution to -78°C again, N,N-dimethylformamide was added. The solution was allowed to warm to room temperature overnight. Dilute hydrochloric acid (0.5N, 200 mL) was added. The solution was diluted with ethyl acetate (3 x 200 mL). The combined ethyl acetate solution was washed with brine (100 mL) and extracted with sodium sulfate (1 L). The solution was filtered and concentrated. The residue was purified by silica gel chromatography. Purification by HPLC, eluting with ethyl acetate / hexane (0-40%), yielded 4-chloro-6-(trifluoromethyl-2-methyl-2-propanol). (fluoromethyl)pyridine-3-carbaldehyde (5.7 g, 27.22 mmol, 20%) yield).

[0206] Step 2: 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)- Synthesis of fluoromethyl)pyridine-3-carbaldehyde [ka] 2-Chloro-4-(trifluoromethoxy)phenol in acetonitrile (50 mL) (2.79 g, 13.12 mmol), 4-chloro-6-(trifluoromethyl)pyridin To a stirred solution of benzophenone-3-carbaldehyde (2.5 g, 11.93 mmol), potassium carbonate was added. (3.3 g, 23.86 mmol) was added, and the solution was heated at 80° C. for 3 hours. The solution was cooled to room temperature, ethyl acetate (50 mL) was added, and the solution was filtered and concentrated. The residue is purified by silica gel chromatography eluting with ethyl acetate / heptane (0-30%). Purified by 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)-2-(2-chloro-4-(trifluoromethoxy)phenoxy) ... (fluoromethyl)pyridine-3-carbaldehyde (4.6 g, 11.928 mmol, yield The product was obtained as a colorless oil in a yield of 99.98%. 1H NMR (400 MHz, chloroform-d) δ ppm 6.89 (s , 1 H) 7.33 - 7.42 (m, 2 H) 7.49 - 7.55 (m, 1 H) 9.15 (s, 1 H) 10.68 - 10.75 (m, 9 H)

[0207] Step 3: 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl)- Synthesis of fluoromethyl)pyridine-3-carboxylic acid [ka] Monosodium phosphate monohydrate (7.53 g, 54.58 mmol) in water (50 mL) A stirred solution of sodium chlorite (3.7 g, 32.75 mmol) in acetonitrile (50 mL) was added. Then, 4-[2-chloro-4-(trifluoromethoxy)phenyl] [Noxy]-6-(trifluoromethyl)pyridine-3-carbaldehyde (4.21g, 1 0.92 mmol) was added. The solution was stirred at room temperature for 3 hours. Sodium sulfite (aq. Solution, 10%, 0.5 mL) was added. The solution was stirred at room temperature for 30 minutes. The mixture was concentrated. Hydrochloric acid (1N, 2 mL) was added. The white precipitate was collected by filtration. This was diluted with water. Washed, dried and 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-6 -(trifluoromethyl)pyridine-3-carboxylic acid (4.2 g, 10.4 mmol, yield A white solid was obtained with a yield of 95.4%. 1H NMR (400 MHz, chloroform-d) δ ppm 6.88 (s , 1 H) 7.31 (d, J=1.52 Hz, 2 H) 7.48 - 7 .57 (m, 1 H) 9.31 (s, 1 H)

[0208] Step 4: 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[2- (Dimethylamino)-4-pyridyl]-6-(trifluoromethyl)pyridine-3-carbohydrate Synthesis of voxamide [ka] 4-[2-chloro-4-(trifluoromethoxy)phenoxy]phenoxyethanol in DCM (2 mL) at room temperature ci]-6-(trifluoromethyl)pyridine-3-carboxylic acid (50 mg, 0.1200 To a stirred solution of 23.7 mg (0.19 mmol) of oxalyl chloride was added (23.7 mg, 0.19 mmol). DMF (1 drop) was added. The solution was stirred at room temperature for 1 hour. The solution was concentrated. The residue was dissolved in DCM (2 mL) and triethylamine (0.03 mL, 0.25 mmol) ) and N2,N2-dimethylpyridine-2,4-diamine (20.5 mg, 0.15 mm ol) was added. The solution was stirred at room temperature for 1 hour. The solution was washed once with hydrochloric acid (1N, 2 mL). The residue was purified by preparative reverse phase HPLC to give 4-[2-chloro-4-(trimethylsilyl)-2-( ... Fluoromethoxy)phenoxy]-N-[2-(dimethylamino)-4-pyridyl]-6 -(trifluoromethyl)pyridine-3-carboxamide (21 mg, 0.04 mmol (32.4% yield) was obtained as a white solid. 1H NMR (400 MHz, chloroform-d) δ ppm 3.33 (s , 6 H) 6.91 (s, 1 H) 7.37 (d, J=9.85 Hz, 1 H) 7.48 - 7.60 (m, 3 H) 8.03 (s, 1 H) 9.18 (s., 1 H) 10.48 (br. s., 1 H)

[0209] The following compounds were synthesized according to Method J: [ka] [Table 8-1] [Table 8-2] [Table 8-3]

[0210] (Example 83: 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-( 1-Oxidopyridin-1-ium-3-yl)-6-(trifluoromethyl)pyridine -3-carboxamide) [Method K] [ka] 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-pyridyl) -6-(trifluoromethyl)pyridine-3-carboxamide (Example LI-1971, 100 mg, 0.21 mmol) was added to a screw-cap vial and diluted with DCM (5 ml m-CPBA (56 mg, 0.25 mmol) was added and the mixture was allowed to stand at room temperature. The mixture was stirred at rt for 15 min. The volatiles were evaporated under reduced pressure and the residue was purified by preparative reversed-phase HPLC (high p The title compound was obtained as a colorless glass (81 mg, 0.16 mmol, 7 8% yield). MS, ES+ m / z 494 [M+H]+.

[0211] The following compounds were synthesized according to Method K: [ka] [Table 9-1] [Table 9-2] [Table 9-3]

[0212] Example 91: N-[3-(methylsulfonimidoyl)phenyl]-4-[4-(tri ... Fluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide Samid) [Method L] [ka]

[0213] Step 1: 4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl) Synthesis of methyl pyridine-3-carboxylate [ka] Methyl 4-chloro-6-(trifluoromethyl)pyridine-3-carboxylate (1 g, 4. 2 mmol) was added to a 20 mL scintillation vial equipped with a magnetic stir bar and The resulting solution was dissolved in 10 mL of 4-(trifluoromethoxy)phenol (892 mL). g, 5 mmol) and cesium carbonate (2.72 g, 8.34 mmol) were added, and the mixture was The mixture was heated at 50°C for 1 hour. After cooling to room temperature, the mixture was diluted with water (100 mL) and The combined dichloromethane solution was dried over magnesium sulfate and Concentration gave an oil containing the desired product (1.2 g, 3.15 mmol, 75% yield).

[0214] Step 2: 4-[4-(trifluoromethoxy)phenoxy]-6-(trifluoromethyl) Synthesis of pyridine-3-carboxylic acid [ka] In a round-bottom flask equipped with a magnetic stir bar, add 4-[4-(trifluoromethoxy)phenoxy]- 6-(trifluoromethyl)pyridine-3-carboxylate (1.2 g, 3.15 mm 100 ml) was added and dissolved in THF (9 mL) and water (1 mL). The mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (200 mL). The resulting solution was then made strongly acidic by careful addition of 6N HCl. The resulting solution was extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to give a clear oil. The resulting product was 1.1 g (3.0 mmol), which solidified on standing and required further purification. Used without further analysis. MS, ES+ m / z 368 [M+H]+.

[0215] Step 3: N-[3-(methylsulfonimidoyl)phenyl]-4-[4-(trifluoromethyl)phenyl]-4-(methylsulfonimidoyl)phenyl]-4-(trifluoromethyl ... (Oromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide Synthesis of Do [ka] Screw cap vial with 4-[4-(trifluoromethoxy)phenoxy]-6- (Trifluoromethyl)pyridine-3-carboxylic acid (150 mg, 0.41 mmol) Add DMF (3 mL) and triethylamine (115 μL, 0.82 mmol). and HBTU (186 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for 10 minutes. 3-(methylsulfonimidoyl)aniline (70 mg, 0.41 mol) was added, Stirring was continued for another 12 hours. The crude mixture was purified by preparative reversed-phase HPLC (high pH method). This afforded the desired product (97 mg, 0.19 mmol, 46% yield) as a beige solid. MS, ES+ m / z 520.0 [M+H]+. 1H NMR ( 400 MHz, DMSO-d6) δ ppm 3.06 (s, 3 H) 4. 25 (s, 1 H) 7.26 (s, 1 H) 7.44 - 7.50 (m , 2 H) 7.51 - 7.57 (m, 2 H) 7.60 (t, J=7 .96 Hz, 1 H) 7.69 (d, J=7.83 Hz, 1 H) 7. 90 (d, J=8.08 Hz, 1 H) 8.35 (t, J=1.89 H z, 1 H) 8.98 (s, 1 H)

[0216] The following compounds were synthesized according to Method L: [ka] [Table 10]

[0217] Example 93: 4-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonyl)- [sulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide Mid) [Method M] [ka]

[0218] Step 1: 4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl ) Synthesis of methyl pyridine-3-carboxylate [ka] Methyl 4-chloro-6-(trifluoromethyl)pyridine-3-carboxylate (1 g, 4. 2 mmol) was placed in a round-bottom flask and dissolved in acetonitrile (10 mL). sodium (2.7 g, 8.3 mmol) and 4-fluoro-2-methyl-phenol (63 2 mg, 5.0 mmol) was added and the mixture was heated to 50°C with stirring for 1 hour. After cooling to rt, the mixture was diluted with water (150 mL) and extracted with dichloromethane. The dichloromethane extract was dried over magnesium sulfate and concentrated under reduced pressure to a clear oil (1 The resulting product was used without further purification (0.13 g, 3.42 mmol, 82% yield). Used.

[0219] Step 2: 4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl ) Synthesis of pyridine-3-carboxylic acid [ka] 4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine Methyl 3-carboxylate (1.4 g, 4.2 mmol) was placed in a round-bottom flask and dissolved in THF( The solution was dissolved in sodium hydroxide (960 mg, 21 mmol) and water (2 mL). ) was added and the mixture was stirred at room temperature for 1 hour. The crude mixture was diluted with water (200 mL). The resulting cloudy solution was extracted with dichloromethane and The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under reduced pressure to a colorless A solid (980 mg, 3.1 mmol, 74% yield) was obtained, which was purified without further purification. It was used extensively.

[0220] Step 3: 4-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonyl) [(trifluoromethyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide Synthesis of [ka] 4-(4-fluoro-2-methyl-phenoxy)-6-(trifluoromethyl)pyridine 150 mg, 0.48 mmol) of α-3-carboxylic acid was added to a screw cap equipped with a magnetic stir bar. The solution was placed in a top vial and dissolved in DMF (3 mL). Triethylamine (133 μL, HBTU (217 mg, 0.57 mmol) was added, and the mixture was heated at 47°C for 1 hour. The mixture was stirred at room temperature for 10 minutes. 3-(methylsulfonimidoyl)aniline (81 mg, 0.4 8 mmol) was added and stirring was continued for another 12 hours. The title compound (129 mg, 0.28 mmol, 58% yield) was obtained as a beige solid. The compound was obtained as a methyl group. MS, ES+ m / z 468.0 [M+H]+. 1H NMR (400 MHz, DMSO-d 6) δ ppm 2.13 (s, 3 H) 3.53 (s, 3 H) 5.6 6 - 5.88 (m, 2 H) 6.81 - 6.95 (m, 2 H) 7 .06 - 7.35 (m, 6 H) 9.05 (s, 1 H).

[0221] The following compounds were synthesized according to Method M: [ka] [Table 11]

[0222] The following compounds were synthesized according to Method M: [ka] [Table 12-1] [Table 12-2]

[0223] The following compounds were synthesized according to Method M: [ka] [Table 13-1] [Table 13-2]

[0224] The following compounds were synthesized according to Method M: [ka] [Table 14-1] [Table 14-2]

[0225] Example 109: 2-(4-fluoro-2-methyl-phenoxy)-N-(2-methoxy (4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide [ka]

[0226] Step 1: 2-chloro-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl) Synthesis of pyridine-3-carboxamide [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3-carboxylate in chloroform (5 mL) Carbonyl chloride (250 mg, 1.02 mmol), 2-methoxypyridine-4-amine (127 mg, 1.02 mmol) and DIPEA (446 μL, 2.56 mmol) The mixture was stirred at room temperature for 24 hours. The contents were treated with 10% Na2CO3 and CHCl Extract with 3 (3x), remove the solvent in vacuo, and add 2-chloro-N-(2-methoxy-4-pyridinyl) (290 mg, 0.8 74 mmol, 85.3% yield) was obtained as a pink solid. Used without further purification. MS, ES+ m / z 379.0 [M+H]+.

[0227] Step 2: 2-(4-fluoro-2-methyl-phenoxy)-N-(2-methoxy-4- Synthesis of pyridyl-5-(trifluoromethyl)pyridine-3-carboxamide [ka] 2-Chloro-N-(2-methoxy-4-pyridyl)-5-(trimethylsilyl)-2-(2-chloro ... Fluoromethyl)pyridine-3-carboxamide (84.0 mg, 0.253 mmol) , 4-fluoro-2-methyl-phenol (47.9 mg, 0.380 mmol) and charcoal The mixture was stirred at 80°C for 2 hours. After cooling, the contents were diluted with EtOAc and washed with water (3x), brine (1x), and MgSO The residue was dried over 4°C, filtered, and the solvent removed in vacuo to give a residue which was triturated with 10% MeCN / water. Litturation gave a precipitate, which was collected by filtration, washed with water, dried in vacuo, and 2- (4-Fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridyl)-5 -(Trifluoromethyl)pyridine-3-carboxamide (50.0 mg, 0.119 (mmol, 46.9% yield) as a beige solid. MS, ES+ m / z 422.2 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.99 (s, 1 H), 8.68 (s, 1 H), 8.57 (s, 1 H), 8.11 ( d, J=5.81 Hz, 1 H), 7.18 - 7.30 (m, 4 H) , 7.08 - 7.15 (m, 1 H), 3.85 (s, 3 H), 2 .08 (s, 3 H).

[0228] Example 110: 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo- 1H-pyridin-4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide Do) [ka] 2-(4-fluorophenyl)- ... (2-methyl-phenoxy)-N-(2-methoxy-4-pyridyl)-5-(trifluoromethyl)-2-methyl-phenoxy (2-O-methyl)pyridine-3-carboxamide (50.0 mg, 0.119 mmol) The solution was stirred at 80°C for 18 hours. After cooling, the contents were slowly added to 5% Na2CO3. The aqueous layer was extracted with EtOAc and washed with 5% Na2CO3 (3x), brine (1 x), dried over MgSO4, filtered and the solvent removed in vacuo to give 2-(4-fluoro (2-oxo-1H-pyridin-4-yl)-N-(2-oxo-2-methyl-phenoxy)-5 -(trifluoromethyl)pyridine-3-carboxamide (26.0 mg, 0.0638 4 mmol, yield 53.8%) as a brown solid. MS, ES+ m / z 408 .0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1 H), 8.64 (dd, J=2.53, 1.01 Hz, 1 H), 8.5 9 (d, J=2.53 Hz, 1 H), 8.42 - 8.44 (m, 1 H), 7.98 (dt, J=7.58, 1.89 Hz, 1 H), 7. 66 - 7.73 (m, 2H), 7.08 - 7.16 (m, 3H) , 3.23 (s, 3 H), 2.07 (s, 6 H).

[0229] Example 111: 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-N- (3-methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0230] Step 1: 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3 Synthesis of methyl carboxylate [ka] Methyl 5-bromo-2-chloronicotinate (100 mg, 0.3 mL) in MeCN (3 mL) 99 mmol), 4-fluoro-2-methoxyphenol (47.8 μL, 0.419 m A mixture of 1000 mg of cesium carbonate (325 mg, 0.998 mmol) and cesium carbonate (325 mg, 0.998 mmol) was heated at 50°C for 20 The contents were diluted with EtOAc and diluted with 2% Na2CO3 (3x), brine (1 x), dried over MgSO4, filtered and the solvent removed in vacuo to give 5-bromo-2- Methyl (4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylate (90. 7 mg, 0.255 mmol, 63.8% yield) was obtained as a brown solid. This was carried forward without further purification. MS, ES+ m / z 355.9 / 357.9 [M +H]+. 1H-NMR (400 MHz, DMSO-d6) δ 8.40 (s, 2 H ), 7.18 (dd, J=8.84, 5.81 Hz, 1 H), 7.08 (dd, J=10.74, 2.91 Hz, 1 H), 6.80 (td, J=8.46, 2.78 Hz, 1 H), 3.87 (s, 3 H), 3. 69 (s, 3 H).

[0231] Step 2: 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)pyridine-3 -Synthesis of carboxylic acids [ka] 5-Bromo-2-(4-fluoro-2-methoxyphenyl)-2-(4-bromo-2-methoxyphenyl) ...bromo-2-methoxyphenyl) -phenoxy)pyridine-3-carboxylate (65 mg, 0.183 mmol) and A mixture of lithium hydroxide monohydrate (38.3 mg, 0.913 mmol) was heated at 50°C for 2 hours. After cooling, 6N HCl was carefully added to lower the pH to pH 5. After that, the precipitate was collected by filtration, washed with cold water, dried in vacuo, and (2-methoxy-phenoxy)pyridine-3-carboxylic acid (39.3 mg, 0.11 5 mmol, 62.9% yield) was obtained as a white solid. MS, ES+ m / z 341 .9 / 343.9 [M+H]+. 1H-NMR (400 MHz, DMSO- d6) δ 13.56 (br. s., 1 H), 8.33 - 8.37 ( m, 2 H), 7.17 (dd, J=8.72, 5.94 Hz, 1 H) , 7.07 (dd, J=10.86, 2.78 Hz, 1 H), 6.79 (td, J=8.46, 2.78 Hz, 1 H), 3.69 (s, 3 H).

[0232] Step 3: 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3- Synthesis of methylsulfonylphenyl)pyridine-3-carboxamide [ka] HBTU (42.7 mg, 0.113 mmol) in chloroform (3 mL), DIPE A (39.2 μL, 0.225 mmol), 5-bromo-2-(4-fluoro-2-methanone) (oxy-phenoxy)pyridine-3-carboxylic acid (35 mg, 0.102 mmol) and 3 -methylsulfonylaniline (18.4 mg, 0.107 mmol) at room temperature. The contents were treated with 5% Na2CO3 and extracted with CHCl3 (3x). The solvent was removed in vacuo to give a residue which was purified by automated normal phase chromatography (0-100%). Purify with EtOAc / heptane, 4 g silica gel cartridge) to obtain 5-bromo-2-(4 -fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyri Zine-3-carboxamide (13.0 mg, 0.0262 mmol, 25.6% yield) was obtained as a white solid. MS, ES+ m / z 494.9 / 496.9 [M+H ]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1 H), 8.40 - 8.42 (m, 1 H), 8.34 - 8.36 (m , 2 H), 7.95 - 7.98 (m, 1 H), 7.64 - 7.7 1 (m, 2 H), 7.29 (dd, J=8.84, 6.06 Hz, 1 H), 7.08 (dd, J=10.74, 2.91 Hz, 1 H), 6 .82 (td, J=8.59, 3.03 Hz, 1 H), 3.70 (s, 3 H), 3.22 (s, 3 H).

[0233] Example 112: 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy) )-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide) [ka]

[0234] Step 1: Synthesis of methyl 2-chloro-5-cyclopropyl-pyridine-3-carboxylate [ka] Methyl 5-bromo-2-chloronicotinate (200 ml) in 1,4-dioxane (5 mL) g, 0.799 mmol) was added to a solution of cyclopropylboronic acid (206 mg, 2.40 m mol), tripotassium phosphate (508 mg, 2.40 mmol) and tetrakis(trifluoromethyl) (phenylphosphine)palladium(0) (46.1 mg, 0.0399 mmol) was added. The mixture was heated in a microwave reactor at 100°C for 30 minutes. The reaction mixture was diluted with EtOAc and washed with water (1x), 5% NH4Cl (1x), Wash with water (1x), brine (1x), dry over MgSO4, filter, and remove the solvent in vacuo. Evaporation gave a yellow residue which was purified by automated normal phase chromatography (0-100% EtOAc / heptane, 12 g silica gel cartridge) to obtain 2-chloro-5-cyclopropane. Methyl pyridine-3-carboxylate (73.0 mg, 0.345 mmol, yield 43 0.2%) as a colorless oil. MS, ES+ m / z 212.0 [M+H]+ .1H-NMR (400 MHz, DMSO-d6) δ 8.41 (d, J=2.53 Hz, 1 H), 7.86 (d, J=2.53 Hz, 1 H) ), 3.87 (s, 3 H), 2.05 (tt, J=8.46, 5.05 Hz, 1 H), 1.02 - 1.09 (m, 2 H), 0.79 - 0.85 (m, 2 H).

[0235] Step 2: 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)pyridine Synthesis of methyl azide-3-carboxylate [ka] 2-Chloro-5-cyclopropyl-pyridine-3-carboxylic acid methyl in MeCN (2 mL) ethyl (71 mg, 0.336 mmol), 4-fluoro-2-methoxyphenol (4 7.8 μL, 0.419 mmol) and cesium carbonate (327.91 mg, 1.01 mm The mixture was stirred at 80°C for 24 hours. After cooling, the solvent was removed under a stream of N2. The distillate was treated with water and stirred vigorously for 2 hours. The precipitate was collected by filtration, washed with water, and dried under vacuum. 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)pyridine Methyl 3-carboxylate (20.0 mg, 0.0630 mmol, 18.8% yield) was added to brown rice. This material was used without further purification. MS, ES+ m / z 318.0 [M+H]+.

[0236] Step 3: 5-cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)pyridine Synthesis of cin-3-carboxylic acid [ka] 5-Cyclopropyl-2-(4-furan) in THF (2 mL) and methanol (0.2 mL) Fluoro-2-methoxy-phenoxy)pyridine-3-carboxylate methyl (20.1 mg , 0.0633 mmol) and lithium hydroxide monohydrate (10.0 mg, 0.238 mm The mixture of (100%) and (20%) was stirred at room temperature for 5 days (for convenience). The solvent was removed under a stream of N2, and the contents were The mixture was diluted with water (3 mL). 6N HCl was carefully added to lower the pH to 5. The mixture was stirred for 3 hours. After stirring, the precipitate was collected by filtration, washed with water, dried in vacuo, and 5-cyclopropyl-2 -(4-fluoro-2-methoxy-phenoxy)pyridine-3-carboxylic acid (9.5 mg , 0.031 mmol, 49.4% yield) as an off-white solid. Used without further purification. MS, ES+ m / z 304.0 [M+H] +.

[0237] Step 4: 5-Cyclopropyl-2-(4-fluoro-2-methoxy-phenoxy)-N Synthesis of -(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka] 5-Cyclopropyl-2-(4-fluoro-2-methoxy)-2-(4-methyl-2-methylpropional) in chloroform (0.5 mL) (Ci-phenoxy)pyridine-3-carboxylic acid (9.5 mg, 0.0313 mmol), H BTU (14.3 mg, 0.0376 mmol), 3-methylsulfonylaniline (5. 9 mg, 0.0345 mmol) and DIPEA (16.4 μL, 0.0940 mmol) The mixture was stirred at room temperature for 3 days (for convenience). The contents were diluted with EtOAc and added water (3 x), washed with brine (1x), dried over MgSO4, filtered and the solvent removed in vacuo. The residue was purified by automated normal phase chromatography (0-100% EtOAc / heptane, Purify on a 4g silica gel cartridge and 5-cyclopropyl-2-(4-fluoro-2 -Methoxy-phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide Voxamide (2.6 mg, 0.0057 mmol, 18.2% yield) was obtained as a white solid. MS, ES+ m / z 457.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.73 (s, 1 H), 8.40 - 8.43 (m, 1 H), 8.02 (d, J=2.53 Hz, 1 H) , 7.97 (dt, J=7.07, 2.02 Hz, 1 H), 7.75 (d, J=2.53 Hz, 1 H), 7.63 - 7.70 (m, 2 H ), 7.27 (dd, J=8.72, 5.94 Hz, 1 H), 7.05 (dd, J=10.74, 2.91 Hz, 1 H), 6.81 (td, J=8.46, 3.03 Hz, 1 H), 3.70 (s, 3 H), 3. 22 (s, 3 H), 1.93 - 2.01 (m, 1 H), 0.95 - 1.00 (m, 2 H), 0.72 - 0.77 (m, 2 H).

[0238] Example 113: 2-(4-fluoro-2-methyl-phenoxy)-N-(3-methylsulfonyl) (sulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide [Method N] [ka]

[0239] Step 1: 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl ) Synthesis of pyridine-3-carboxylic acid [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3-carbohydrate in MeCN (5 mL) carboxylic acid (497 mg, 2.20 mmol), 4-fluoro-2-methyl-phenol (30 6 mg, 2.42 mmol) and cesium carbonate (1.79 g, 5.51 mmol) The solution was stirred at 80°C for 5 hours, and then stirred at room temperature for 4 days (for convenience). The residue was dissolved in water (10 mL) and the pH was adjusted to 5 by careful addition of 6N HCl. After stirring for 3 hours, the precipitate was collected by filtration, washed with water, and dried in vacuo to give 2-(4 -fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate The carboxylic acid (407.5 mg, 1.293 mmol, 58.7% yield) was obtained as a beige solid MS, ES+ m / z 316.0 [M+H]+.

[0240] Step 2: 2-(4-fluoro-2-methyl-phenoxy)-N-(3-methylsulfonyl) Synthesis of (phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide [ka] 2-(4-fluoro-2-methyl-phenoxy)-5-(trifluoromethyl)-2-propanol in chloroform (2 mL) (trifluoromethyl)pyridine-3-carboxylic acid (100 mg, 0.317 mmol), 3 -Methylsulfonylaniline (59.8 mg, 0.349 mmol), HBTU (132 mg, 0.349 mmol) and DIPEA (138 μL, 0.793 mmol) The mixture was stirred at room temperature for 18 hours. The solvent was removed under a stream of N2, and the residue was dissolved in water / MeOH ( The mixture was briefly sonicated and then stirred at room temperature for 4 hours. The precipitate was collected by filtration, washed with water, dried in vacuo, and purified by filtration to give 2-(4-fluoro-2-methyl- (3-methylsulfonylphenyl)-5-(trifluoromethyl-phenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethyl (I)pyridine-3-carboxamide (121.7 mg, 0.260 mmol, yield 81. 9%) as a brown solid. MS, ES+ m / z 469.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 11.05 (s, 1 H), 8.67 - 8.69 (m, 1 H), 8.57 (d, J=2. 53Hz, 1H), 8.40 - 8.42 (m, 1H), 7.97 (dt, J=7.58, 1.89 Hz, 1 H), 7.65 - 7.73 (m, 2 H), 7.27 (dd, J=8.84, 5.05 Hz, 1 H ), 7.21 (dd, J=9.35, 3.03 Hz, 1 H), 7.12 (td, J=8.78, 3.16 Hz, 1 H), 3.23 (s, 3 H), 2.09 (s, 3 H).

[0241] The following compounds were synthesized according to Method M: [ka] [Table 15-1] [Table 15-2]

[0242] Example 117: 2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N- (3-methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0243] Step 1: 2-chloro-6-methyl-N-(3-methylsulfonylphenyl)pyridine- Synthesis of 3-carboxamides [ka] HBTU (243 mg, 0.641 mmol), DIPEA in chloroform (5 mL) (223 μL, 1.28 mmol), 2-chloro-6-methylnicotinic acid (100 mg, 0.583 mmol) and 3-methylsulfonylaniline (105 mg, 0.613 mmol) The mixture was stirred at room temperature for 48 hours. The contents were treated with 5% Na2CO3 and CHCl The solvent was removed in vacuo and the residue was extracted with 2-chloro-6-methyl-N-(3-methyl- (phenylsulfonylphenyl)pyridine-3-carboxamide (175 mg, 0.539 mmol) 1, 92.5% yield) was obtained as a residue, which was used without further purification. S, ES+ m / z 325.0 [M+H]+.

[0244] Step 2: 2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3- Synthesis of methylsulfonylphenyl)pyridine-3-carboxamide [ka] Crude 2-chloro-6-methyl-N-(3-methylsulfonyl) Phenyl)pyridine-3-carboxamide (70.0 mg, 0.216 mmol), 4- Fluoro-2-methoxyphenol (30.7 μL, 0.269 mmol) and sesquioxane carbonate The mixture was stirred at 60°C for 24 hours. The contents were treated with water and stirred at room temperature overnight. The precipitate was collected by filtration, washed with water, and dried in vacuo. Drying and 2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methyl- (Dimethylsulfonylphenyl)pyridine-3-carboxamide (29.0 mg, 0.0674 40 mmol, yield 31.3%) as a beige solid. MS, ES+ m / z 431.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1 H), 8.41 (s, 1 H), 8.04 ( d, J=7.58 Hz, 1 H), 7.96 (d, J=7.07 Hz, 1 H), 7.62 - 7.69 (m, 2 H), 7.33 (dd, J= 8.72, 5.94 Hz, 1 H), 7.05 - 7.13 (m, 2 H ), 6.83 (td, J=8.46, 3.03 Hz, 1 H), 3.71 (s, 3 H), 3.22 (s, 3 H), 2.30 (s, 3 H).

[0245] Example 118: 2-(4-fluoro-2-methoxy-phenoxy)-5,6-dimethyl -N-(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0246] Step 1: 2-chloro-5,6-dimethyl-N-(3-methylsulfonylphenyl)pyridine Synthesis of din-3-carboxamide [ka] 2-Chloro-5,6-dimethyl-pyridine-3-carboxylic acid in chloroform (4 mL) (100 mg, 0.539 mmol), 3-methylsulfonylaniline (96.9 mg, A mixture of HBTU (225 mg, 0.593 mmol) and D IPEA (206.5 μL, 1.19 mmol) was added, and the resulting mixture was incubated at room temperature for 6 days. The solvent was removed under a stream of N2 and the residue was dissolved in water / MeOH (4:1). The mixture was briefly sonicated and then stirred at room temperature for 18 hours. The precipitate was collected by filtration, washed with water, dried in vacuo, and purified by filtration using 2-chloro-5,6-dimethyl -N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (137 mg, 0.404 mmol, 75.1% yield) was obtained as a beige solid. MS, ES+ m / z 339.0 [M+H]+. 1H-NMR (400 MHz, DMS O-d6) δ 10.96 (s, 1 H), 8.37 (s, 1 H), 7 .94 (d, J=7.33 Hz, 1 H), 7.88 (s, 1 H), 7.64 - 7.72 (m, 2 H), 3.23 (s, 3 H), 2.4 8 (s, 3 H), 2.31 (s, 3 H).

[0247] Step 2: 2-(4-fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N- Synthesis of (3-methylsulfonylphenyl)pyridine-3-carboxamide [ka] 2-Chloro-5,6-dimethyl-N-(3-methylsulfonyl fluoride) in MeCN (4 mL) (phenyl)pyridine-3-carboxamide (50.0 mg, 0.148 mmol), 4- Fluoro-2-methoxyphenol (17.7 μL, 0.155 mmol) and cesium carbonate The mixture was stirred at 80°C for 10 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure and the residue was treated with water / MeOH (2:1). After sonication, the mixture was stirred at room temperature for 18 hours, and the resulting precipitate was collected by filtration and washed with water. , dried in vacuo, and 2-(4-fluoro-2-methoxy-phenoxy)-5,6-dimethyl -N-(3-methylsulfonylphenyl)pyridine-3-carboxamide (21.0 mg , 0.472 mmol, 32.0% yield) was obtained as a reddish-brown solid. MS, ES+ m / z 445.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1 H), 8.40 (s, 1 H), 7.97 (d, J=7.07 Hz, 1 H), 7.92 (s, 1 H), 7.62 - 7.70 (m, 2 H) , 7.30 (dd, J=8.84, 6.06 Hz, 1H), 7.07 (dd, J=10.74, 2.91 Hz, 1 H), 6.82 (td, J =8.59, 3.03 Hz, 1 H), 3.71 (s, 3 H), 3.2 2 (s, 3 H), 2.25 (br. s., 3 H), 2.24 (br. . s., 3 H).

[0248] Example 119: 5-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N- (3-methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0249] Step 1: 2,5-dichloro-N-(3-methylsulfonylphenyl)pyridine-3-carboxylate Synthesis of ruboxamide [ka] HBTU (217 mg, 0.571 mmol), DIPEA in chloroform (5 mL) (200 μL, 1.15 mmol), 2,5-dichloropyridine-3-carboxylic acid (10 0 mg, 0.521 mmol) and 3-methylsulfonylaniline (93.6 mg, 0. The mixture (547 mmol) was stirred at room temperature for 22 hours. The contents were treated with 5% Na2CO3. The solvent was removed in vacuo and 2,5-dichloro-N-(3- Methylsulfonylphenyl)pyridine-3-carboxamide (150 mg, 0.435 m mol, 83.4% yield) as a semi-solid which was used without further purification. Ta. MS, ES+ m / z 344.8 [M+H]+.

[0250] Step 2: 5-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3- Synthesis of methylsulfonylphenyl)pyridine-3-carboxamide [ka] Crude 2,5-dichloro-N-(3-methylsulfonylphenyl) (I)pyridine-3-carboxamide (59.3 mg, 0.172 mmol), 4-fluoro 2-Methoxyphenol (27.4 μL, 0.241 mmol) and cesium carbonate ( The mixture (168 mg, 0.517 mmol) was stirred at 80°C for 3 hours. After cooling, water was added. After stirring for 1 hour, this material was collected by filtration and washed with water. and dried under vacuum to obtain 5-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N -(3-methylsulfonylphenyl)pyridine-3-carboxamide (21 mg, 0.0 47 mmol, 27.1% yield) was obtained as a beige solid. MS, ES+ m / z 451.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1 H), 8.41 (s, 1 H), 8.25 - 8.31 (m, 2 H), 7.97 (d, J=7.58 Hz, 1 H), 7.64 - 7.72 ( m, 2 H), 7.26 - 7.32 (m, 1 H), 7.08 (d, J=10.86 Hz, 1 H), 6.83 (t, J=8.08 Hz, 1 H), 3.70 (s, 3 H), 3.22 (s, 3 H).

[0251] Example 120: 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methyl (sulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate Ruboxamide) [ka]

[0252] Step 1: 2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate Synthesis of carboxylic acids [ka] 2-Chloro-6,7-dihydro-5H-cyclopentadiene in 2 mL of concentrated sulfuric acid / water (1:1) [b] A solution of pyridine-3-carbonitrile (173 mg, 0.969 mmol) was dissolved in 10 The mixture was stirred at 0°C for 9 hours. After cooling, the contents were added little by little to ice water while stirring. The mixture was stirred for 1 hour. After stirring, the precipitate was collected by filtration, washed with cold water, dried in vacuo, and purified to give 2-chloro-6,7 -dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid (117 mg, 0.5 92 mmol, 61.1% yield) was obtained as a brown solid. MS, ES+ m / z 1 98.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 13.53 (br. s., 1 H), 8.02 (s, 1 H), 2. 93 (q, J=7.24 Hz, 4 H), 2.10 (quin, J=7. 24 Hz, 2 H).

[0253] Step 2: 2-chloro-N-(3-methylsulfonylphenyl)-6,7-dihydro-5 Synthesis of H-cyclopenta[b]pyridine-3-carboxamide [ka] 2-Chloro-6,7-dihydro-5H-cyclopenta[b] in chloroform (4 mL) Pyridine-3-carboxylic acid (114 mg, 0.577 mmol), 3-methylsulfonyl Aniline (104 mg, 0.607 mmol) and HBTU (241 mg, 0.637 mmol) To the mixture of (221 μL, 1.27 mmol), DIPEA (221 μL, 1.27 mmol) was added. The mixture was stirred at room temperature for 5 days (for convenience). The solvent was removed under a stream of N2 and the residue was dissolved in water / Methyl The mixture was briefly sonicated and then stirred at room temperature for 1 hour. The resulting precipitate was collected by filtration, washed with water, dried in vacuo, and purified to give 2-chloro- N-(3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclopenta[b] Pyridine-3-carboxamide (147.6 mg, 0.421 mmol, 72.9% yield) ) as a brown solid which was used without further purification. MS, ES+ m / z 351.1 [M+H]+.

[0254] Step 3: 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfo) (6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylate Synthesis of samides [ka] 2-Chloro-N-(3-methylsulfonylphenyl)-6,7 in MeCN (3 mL) -dihydro-5H-cyclopenta[b]pyridine-3-carboxamide (50.0 mg, 0.143 mmol), 4-fluoro-2-methoxyphenol (17.1 μL, 0.1 A mixture of cesium carbonate (102 mg, 0.313 mmol) and cesium carbonate (102 mg, 0.313 mmol) was heated at 80°C. The solvent was removed under a stream of N2, and the residue was treated with water / MeOH (2:1). The mixture was briefly sonicated and then stirred at room temperature for 24 hours. The product was collected by filtration, washed with water, dried in vacuo, and purified by filtration to give 2-(4-fluoro-2-methoxy- (3-methylsulfonylphenyl)-6,7-dihydro-5H-cyclophenyl Penta[b]pyridine-3-carboxamide (24 mg, 0.053 mmol, yield 36 0.9%) as a brown solid. MS, ES+ m / z 457.1 [M+H] +. 1H-NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1 H), 8.42 (br. s., 1 H), 7.96 (s, 2 H) , 7.63 - 7.69 (m, 2H), 7.28 - 7.33 (m, 1 H), 7.05 - 7.10 (m, 1 H), 6.79 - 6.86 (m, 1 H), 3.72 (s, 3 H), 3.22 (s, 3 H), 2.89 (t, J=7.20 Hz, 2H), 2.75 (t, J=7.7 1 Hz, 2 H), 2.01 - 2.11 (m, 2 H).

[0255] Example 121: N-(3-methylsulfinylphenyl)-2-[4-(trifluoromethyl)-2-(phenyl)-2 ... Methoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide [Method O] [ka]

[0256] Step 1: 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl) Synthesis of pyridine-3-carboxylic acid [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3-carbohydrate in MeCN (5 mL) carboxylic acid (510 mg, 2.26 mmol), 4-(trifluoromethoxy)phenol (3 A mixture of cesium carbonate (1.84 g, 5.65 mmol) and cesium carbonate (2.2 μL, 2.49 mmol) The mixture was stirred at 80°C for 5 hours, and then stirred at room temperature for 4 days (for convenience). The residue was treated with water / MeOH (5:1). The mixture was briefly sonicated. After that, the mixture was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. Dry and 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl ) pyridine-3-carboxylic acid (604 mg, 1.65 mmol, 72.8% yield) Obtained as a white solid. MS, ES+ m / z 368.0 [M+H]+.

[0257] Step 2: N-(3-methylsulfinylphenyl)-2-[4-(trifluoromethyl)phenyl]- Synthesis of [(c)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide [ka] 2-[4-(trifluoromethoxy)phenoxy]-5-( (trifluoromethyl)pyridine-3-carboxylic acid (35.0 mg, 0.0953 mmol ), 3-methylsulfinylaniline (16.3 mg, 0.105 mmol), HBT U (39.8 mg, 0.105 mmol) and DIPEA (41.5 μL, 0.238 m The mixture (mol) was stirred at room temperature for 3 days (for convenience). The solvent was removed under a stream of N2, and the residue was The distillate was treated with water / MeOH (3:1). This mixture was briefly sonicated and then cooled to room temperature. The resulting precipitate was collected by filtration, washed with water, dried under vacuum, and then heated under N (3-methylsulfinylphenyl)-2-[4-(trifluoromethoxy)phenoxy] ]-5-(trifluoromethyl)pyridine-3-carboxamide (39.0 mg, 0.0 773 mmol, 81.1% yield) was obtained as a beige solid. MS, ES+ m / z 505.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1 H), 8.72 (d, J=1.52 Hz, 1 H), 8.56 (d, J =2.53 Hz, 1 H), 8.14 (s, 1 H), 7.83 (d, J=7.58 Hz, 1 H), 7.58 (t, J=7.83 Hz, 1 H ), 7.40 - 7.52 (m, 5 H), 2.75 (s, 3 H).

[0258] The following compounds were synthesized according to Method O: [ka] [Table 16-1] [Table 16-2] [Table 16-3]

[0259] Example 130: N-[3-(methylsulfonimidoyl)phenyl]-2-[4 ... [trifluoromethoxy]phenoxy]-5-(trifluoromethyl)pyridine-3-carbo oxamide, enantiomer A) [ka] Racemic N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethyl) (trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (Example LI-1859) was added to 5- Chiralpak IG column with a mobile phase consisting of a 40% gradient Separation by column chromatography T = First eluting enantiomer at 1.46 min MS, ES+ m / z, 520.8 (M+H)+. 1H NMR (4 00 MHz, DMSO-d6) δ ppm 3.07 (s, 3 H) 4.2 7 (s, 1 H) 7.39 - 7.54 (m, 4 H) 7.62 (t, J=7.83 Hz, 1H) 7.70 (dt, J=7.96, 1.20 Hz, 1 H) 7.90 -8.02 (m, 1 H) 8.38 (t, J= 1.89 Hz, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 8 .72 (d, J=1.52 Hz, 1 H) 11.01 (s, 1 H)

[0260] Example 131: N-[3-(methylsulfonimidoyl)phenyl]-2-[4 ... [trifluoromethoxy]phenoxy]-5-(trifluoromethyl)pyridine-3-carbo oxamide, enantiomer B) [ka] Racemic N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethyl) (trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (Example LI-1859) was added to 5- Chiralpak IG column with a mobile phase consisting of a 40% gradient Separation by column chromatography T = First eluting enantiomer at 1.98 min MS, ES+ m / z, 520.8 (M+H)+. 1H NMR (4 00 MHz, DMSO-d6) δ ppm 3.07 (s, 3 H) 4.2 7 (s, 1 H) 7.39 - 7.54 (m, 4 H) 7.62 (t, J=7.83 Hz, 1H) 7.70 (dt, J=7.96, 1.20 Hz, 1 H) 7.90 -8.02 (m, 1 H) 8.38 (t, J= 1.89 Hz, 1 H) 8.57 (d, J=2.53 Hz, 1 H) 8 .72 (d, J=1.52 Hz, 1 H) 11.01 (s, 1 H).

[0261] Example 132: N-(1-oxidepyridin-1-ium-3-yl)-2-[4-( Trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-chlor Voxamide) [Method P] [ka]

[0262] Step 1: 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl) Synthesis of pyridine-3-carboxylic acid (intermediate ABC) [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3-carbohydrate in MeCN (5 mL) carboxylic acid (510 mg, 2.26 mmol), 4-(trifluoromethoxy)phenol (3 A mixture of cesium carbonate (1.84 g, 5.65 mmol) and cesium carbonate (2.2 μL, 2.49 mmol) The mixture was stirred at 80°C for 5 hours, and then stirred at room temperature for 4 days (for convenience). The residue was treated with water / MeOH (5:1). The mixture was briefly sonicated. After that, the mixture was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. Dry and 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl ) pyridine-3-carboxylic acid (604 mg, 1.65 mmol, 72.8% yield) Obtained as a white solid. MS, ES+ m / z 368.0 [M+H]+.

[0263] Step 2: N-(3-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]- Synthesis of 5-(trifluoromethyl)pyridine-3-carboxamide [ka] 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridin Benzene-3-carboxylic acid (250 mg, 0.68 mmol) was added to a screw cap equipped with a magnetic stir bar. The solution was added to a cap vial and dissolved in dichloromethane (2.5 mL). Add 1 drop of ethanol (72 μL, 0.82 mmol), followed by 1 drop of DMF, and stir the mixture for 1 h. 3-aminopyridine (96 mg, 1.0 mmol) and trimethylamine (19 0 μL, 1.36 mmol) was added dropwise as a solution in DCM (2.5 mL). The volatiles were evaporated and the residue was purified by preparative reversed-phase HPLC (high pH method) to give N-(3-pyridinyl)- Lysyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl (I)pyridine-3-carboxamide was obtained as a colorless glass (266 mg, 0.6 mmol). l, yield 88%). MS, ES+ m / z 368.0 [M+H]+. 1H N MR (400 MHz, DMSO-d6) δ ppm 7.40 - 7.53 (m, 5 H) 8.18 (ddd, J=8.34, 2.53, 1.52 H z, 1 H) 8.36 (dd, J=4.55, 1.52 Hz, 1 H) 8.55 - 8.60 (m, 1H) 8.73 (dd, J=2.53, 1. 01 Hz, 1 H) 8.87 (d, J=2.02 Hz, 1 H) 10. 88 (s, 1 H)

[0264] Step 3: N-(1-oxidepyridin-1-ium-3-yl)-2-[4-(trifluoromethyl)-2-(2-methyl-4-pyridin-1-yl)-2 ...trifluoromethyl)-2-(trifluoromethyl)-2-(trifluoromethyl)-2-(trifluoromethyl)-2-(trifluoromethyl)-2 [Fluoromethoxy]phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide Synthesis of mido [ka] N-(3-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenoxy fluoromethyl)pyridine-3-carboxamide (100 mg, 0.23 mmol) was It was added to a screw-cap vial equipped with a stir bar and dissolved in DCM (5 mL). mCPBA (61 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for 15 minutes. The volatiles were evaporated under reduced pressure and the resulting residue was purified by preparative reversed-phase HPLC (high pH method). The title compound was obtained as a colorless glass (69 mg, 0.15 mmol, 67% yield). MS, ES+ m / z 460.0 [M+H]+. 1H NMR (400 M Hz, DMSO-d6) δ ppm 7.38 - 7.60 (m, 6 H) 8.05 (ddd, J=6.32, 1.77, 1.01 Hz, 1 H) 8 .59 (d, J=2.53 Hz, 1 H) 8.71 - 8.84 (m, 2 H) 11.04 (s, 1 H).

[0265] The following compounds were synthesized according to Method P: [ka] [Table 17-1] [Table 17-2] [Table 17-3]

[0266] Example 141: N-(1-oxidepyridin-1-ium-4-yl)-2-[4-( Trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridine-3-chlor Voxamide) [ka] N-(4-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethoxy)phenoxy fluoromethyl)pyridine-3-carboxamide (Example 129, 100 mg, 0.23 (mmol) was added to a screw-top vial equipped with a magnetic stir bar and dissolved in DCM (5 mL). m-CPBA (61 mg, 0.27 mmol) was added and the mixture was stirred at room temperature for 15 minutes. The volatiles were evaporated under reduced pressure and the resulting residue was purified by preparative reverse phase HPLC ( The desired product was obtained as a colorless glass (55 mg, 0.12 mm ol, 53% yield). MS, ES+ m / z 460.0 [M+H]+. 1H N MR (400 MHz, DMSO-d6) δ ppm 7.38 - 7.55 (m, 4 H) 7.69 - 7.80 (m, 2 H) 8.15 - 8.2 6 (m, 2 H) 8.58 (d, J=2.53 Hz, 1 H) 8.73 (d, J=1.26 Hz, 1 H) 11.16 (s, 1 H).

[0267] Example 142: 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N- (3-Methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carbo oxamide) [Method Q] [ka]

[0268] Step 1: 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)- Synthesis of fluoromethyl)pyridine-3-carboxylic acid [ka] 2-Chloro-5-(trifluoromethyl)pyridine-3-carbohydrate in MeCN (2 mL) carboxylic acid (150 mg, 0.665 mmol), 2-chloro-4-(trifluoromethoxy) Phenol (141 mg, 0.665 mmol) and cesium carbonate (433 mg, 1.3 The mixture (3 mmol) was stirred at 80°C for 68 hours. After cooling, the contents were diluted with 20 mL of water. The mixture was diluted and acidified to pH 6 by careful addition of 2N HCl. The precipitate was collected by filtration and washed with water. The resulting solution was washed, dried under vacuum, and purified by 2-[2-chloro-4-(trifluoromethoxy)phenoxy]- 5-(trifluoromethyl)pyridine-3-carboxylic acid (149.5 mg, 0.372 m mol, yield 56.0%) as a beige solid. MS, ES+ m / z 4 01.9 [M+H]+.

[0269] Step 2: 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3- Methylsulfonylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide Synthesis of Do [ka] 2-[2-chloro-4-(trifluoromethoxy)phenoxy]phenoxyethanol in chloroform (2 mL) ci]-5-(trifluoromethyl)pyridine-3-carboxylic acid (33.4 mg, 0.08 32 mmol), 3-methylsulfonylaniline (15.7 mg, 0.0915 mmol ), HBTU (34.7 mg, 0.0915 mmol) and DIPEA (36.2 μL, The mixture was stirred at room temperature for 20 hours. The solvent was removed under a stream of N2. The residue was reacted with water / MeOH (4:1). After briefly sonicating the mixture, The mixture was stirred at room temperature overnight, and the resulting precipitate was collected by filtration, washed with water, and dried in vacuo to give 2- [2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (trifluoromethyl)pyridine-3-carboxamide (34.8m g, 0.0627 mmol, 75.4% yield) as a beige solid. MS ES+ m / z 554.9 [M+H]+. 1H-NMR (400 MHz, D MSO-d6) δ 11.07 (s, 1 H), 8.74 (br. s., 1 H), 8.64 (d, J=2.27 Hz, 1 H), 8.40 (s, 1 H), 7.99 (d, J=7.58 Hz, 1 H), 7.81 (d , J=2.53 Hz, 1 H), 7.65 - 7.74 (m, 3 H), 7.52 - 7.57 (m, 1 H), 3.23 (s, 3 H).

[0270] The following compounds were synthesized according to Method Q: [ka] [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5] [Table 18-6] [Table 18-7] [Table 18-8] [Table 18-9]

[0271] Example 171: 2-(2,4-dimethoxyphenoxy)-N-[3-(N,S-dimethyl [(trifluoromethyl)phenyl]-5-((trifluoromethyl)pyridine-3-carbo oxamide) [Method R] [ka]

[0272] Step 1: 2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)pyridin Synthesis of benzo-3-carboxylic acid [ka] In a round-bottom flask equipped with a magnetic stir bar, add 2-chloro-5-(trifluoromethyl)pyridine 3-carboxylic acid (1.5 g, 6.7 mmol) was added, and acetonitrile (15 mL) was added. Cesium carbonate (4.3 g, 13.3 mmol) and 2,4-dimethoxyphenol (1.1 g, 7.3 mmol) was added and the mixture was refluxed for 12 h. Volatiles were removed under reduced pressure. The mixture was evaporated under reduced pressure and the residue was dissolved in water. 2N HCl was carefully added to adjust the pH to approximately 3. The resulting precipitate was collected by filtration, washed with water and sucked dry to give the desired product. Obtained as a solid (1.75 g, 5.1 mmol, 76% yield). MS, ES+ m / z 344.0 [M+H]+.

[0273] Step 2: 2-(2,4-dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonyl) [(trifluoromethyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide Synthesis of Do [ka] 2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate Carboxylic acid (150 mg, 0.44 mmol) was added to a screw-cap vial and DMSO was added. The solution was dissolved in 3 mL of triethylamine (122 μL, 0.87 mmol) and H BTU (200 mg, 0.52 mmol) was added and the mixture was stirred at room temperature for 10 minutes. -(N,S-dimethylsulfonimidoyl)aniline (81 mg, 0.44 mmol) The mixture was added and stirred for another 12 hours. The mixture was purified by preparative reverse phase HPLC (high pH method) to give the title compound. The compound was obtained as a beige solid (111 mg, 0.22 mmol, 50% yield). S, ES+ m / z 510.4 [M+H]+. 1H NMR (400 MHz , DMSO-d6) δ ppm 2.49 (s, 3 H) 3.12 (s, 3 H) 3.66 - 3.71 (m, 3 H) 3.79 (s, 3 H) 6.57 (dd, J=8.84, 2.78 Hz, 1 H) 6.72 (d, J=2.78Hz, 1H) 7.20 (d, J=8.84Hz, 1H) 7.56 - 7.61 (m, 1 H) 7.62 - 7.69 (m, 1 H) 7.96 (d, J=8.08 Hz, 1 H) 8.32 (s, 1 H ) 8.50 (d, J=2.27 Hz, 1 H) 8.65 (d, J=1.5 2 Hz, 1 H) 10.93 (s, 1 H).

[0274] The following compounds were synthesized according to Method R: [ka] [Table 19]

[0275] Example 174: 2-(2,4-difluorophenoxy)-N-[3-(methylsulfone Imidoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide [Method S] [ka]

[0276] Step 1: 2-(2,4-difluorophenoxy)-5-(trifluoromethyl)pyridin 3-carboxylic acid [ka] In a round-bottom flask equipped with a magnetic stir bar, add 2-chloro-5-(trifluoromethyl)pyridine 3-carboxylic acid (1.5 g, 6.7 mmol) was added, and acetonitrile (15 mL) was added. Cesium carbonate (4.3 g, 13.3 mmol) and 2,4-difluorophenol (952 mg, 7.3 mmol) was added and the mixture was refluxed for 12 h. The solvent was removed under reduced pressure. The resulting residue was dissolved in water, and the pH was adjusted to about 3 by adding 2N HCl. The precipitate was collected by filtration, washed with water, and sucked dry to give the desired product as a white solid. (1.9 g, 2.1 mmol, 91% yield). MS, ES+ m / z 32 0 [M+H]+.

[0277] Step 2: 2-(2,4-difluorophenoxy)-N-[3-(methylsulfonimide) Synthesis of [(2-(2-yl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide [ka] 2-(2,4-difluorophenoxy)-5-(trifluoromethyl)pyridine-3-carboxylate Carboxylic acid (150 mg, 0.44 mmol) was added to a screw-cap vial and DMSO was added. The solution was dissolved in 3 mL of triethylamine (122 μL, 0.87 mmol) and H BTU (200 mg, 0.52 mmol) was added and the mixture was stirred at room temperature for 10 minutes. -(N,S-dimethylsulfonimidoyl)aniline (75 mg, 0.44 mmol) The mixture was added and stirred for another 12 hours. The mixture was purified by preparative reverse phase HPLC (high pH method) to give the title compound. The product was obtained as a beige solid (97 mg, 0.21 mmol, 47% yield). MS , ES+ m / z 472.0 [M+H]+. 1H NMR (400 MH z, DMSO-d6) δ ppm 3.07 (s, 3 H) 7.46 - 7 .59 (m, 2 H) 7.59 - 7.66 (m, 1 H) 7.67 - 7.74 (m, 1 H) 7.96 (d, J=8.08 Hz, 1 H) 8.39 (t, J=1.77 Hz, 1 H) 8.61 (d, J=2.53 Hz, 1 H) 8.72 (d, J=1.52 Hz, 1 H) 11.03 (s, 1 H).

[0278] The following compounds were synthesized according to Method S: [ka] [Table 20]

[0279] Example 177: 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6- Methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0280] Step 1: 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl Synthesis of ethyl 3-pyridinecarboxylate [ka] 2-Chloro-5-cyano-6-methyl-pyridine-3-carvone in MeCN (5 mL) Ethyl acetate (150 mg, 0.668 mmol), 4-fluoro-2-methoxyphenol (95.1 μL, 0.835 mmol) and cesium carbonate (653 mg, 2.00 mmol) The mixture of l) was stirred at 60°C for 1 hour. After cooling, the contents were treated with water and stirred at room temperature overnight. The precipitate was collected by filtration, washed with water, dried in vacuo, and purified to give 5-cyano-2-(4-fluoro- -2-Methoxy-phenoxy)-6-methyl-pyridine-3-carboxylate ethyl (135 mg, 0.409 mmol, 61.2% yield) as a greenish-gray solid. , ES+ m / z 331.0 [M+H]+. 1H-NMR (400 MHz , DMSO-d6) δ 8.64 (s, 1 H), 7.20 (dd, J= 8.97, 5.94 Hz, 1 H), 7.11 (dd, J=10.48, 2.65 Hz, 1 H), 6.82 (td, J=8.46, 2.78 Hz) , 1 H), 4.33 (q, J=7.07 Hz, 2 H), 3.70 ( s, 3 H), 2.46 (s, 3 H), 1.32 (t, J=7.07 Hz, 3 H).

[0281] Step 2: 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl Synthesis of -pyridine-3-carboxylic acid [ka] 5-cyano-2-(4-fluoro-2-methanone) in THF (2 mL) and water (0.1 mL) Ethyl 6-methyl-pyridine-3-carboxylate (135 mg, 0. 409 mmol) and lithium hydroxide monohydrate (18.9 mg, 0.450 mmol) The mixture was stirred at room temperature for 2 hours, the solvent was removed under a stream of N2, and the residue was dissolved in water. The pH was lowered to pH 5 by careful addition of 6N HCl and the product was extracted with CHCl3 (4x). The solvent was removed in vacuo to give a residue which was purified by automated normal phase chromatography (0-100% Et OAc / heptane, 4 g silica gel cartridge) and purified with 5-cyano-2-(4-fluoro-2-methyl-2-propanediol). (fluoro-2-methoxy-phenoxy)-6-methyl-pyridine-3-carboxylic acid (77. 2 mg, 0.255 mmol, 62.5% yield, was obtained as a yellow solid. MS, ES + m / z 303.0 [M+H]+. 1H-NMR (400 MHz, DM SO-d6) δ 13.55 (br. s., 1 H), 8.57 (s, 1 H), 7.19 (dd, J=8.84, 6.06 Hz, 1 H), 7. 11 (dd, J=10.74, 2.91 Hz, 1 H), 6.82 (td , J=8.53, 2.91 Hz, 1 H), 3.70 (s, 3 H), 2.44 (s, 3 H).

[0282] Step 3: 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl Synthesis of N-(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka] 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)propanol in chloroform (3 mL) (iii)-6-methyl-pyridine-3-carboxylic acid (75.0 mg, 0.248 mmol), 3-Methylsulfonylaniline (46.7 mg, 0.273 mmol), HBTU (11 A mixture of 3 mg of PEG-400 (0.298 mmol) and DIPEA (130 μL, 0.744 mmol) The mixture was stirred at room temperature for 19 hours. The contents were diluted with EtOAc and washed with water (3x), brine, and hexane. (1x), dried over MgSO4, filtered, and the solvent removed in vacuo to give a residue which The analysis was performed using automated normal phase chromatography (0-100% EtOAc / heptane, 4g silica gel column) Purify with 5-cyano-2-(4-fluoro-2-methoxy-phenoxy) -6-methyl-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide ( The compound (49.0 mg, 0.108 mmol, 43.4% yield) was obtained as a pale yellow solid. , ES+ m / z 456.0 [M+H]+. 1H-NMR (400 MHz , DMSO-d6) δ 10.89 (s, 1 H), 8.57 (s, 1 H), 8.39 (s, 1 H), 7.94 - 7.99 (m, 1 H), 7.64 - 7.72 (m, 2 H), 7.31 (dd, J=8.84, 5.81 Hz, 1 H), 7.11 (dd, J=10.74, 2.91 Hz, 1 H), 6.84 (td, J=8.53, 2.91 Hz, 1 H ), 3.71 (s, 3 H), 3.22 (s, 3 H).

[0283] Example 178: 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6 -Methoxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0284] Step 1: 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-meth Synthesis of methyl oxy-pyridine-3-carboxylate [ka] 2-Chloro-5-fluoro-6-methoxy-pyridine-3-carboxamide in MeCN (8 mL) Methyl benzoate (200 mg, 0.911 mmol), 4-fluoro-2-methoxyphenoxy ethanol (114 μL, 1.00 mmol) and cesium carbonate (742 mg, 2.28 mmol) The mixture was stirred at 80°C for 3 hours, and then cooled to room temperature with stirring. 1 mL) and methanol (5 mL) were added, and the resulting mixture was sonicated briefly and then incubated for 4 hours. The precipitate was collected by filtration, washed with water, dried in vacuo, and the 5-fluoro- 2-(4-Fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3-chloride Methyl benzoate (237 mg, 0.727 mmol, 79.9% yield) was obtained as a beige solid. MS, ES+ m / z 326.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=10.11 Hz , 1 H), 7.18 (dd, J=8.72, 5.94 Hz, 1 H), 7.09 (dd, J=10.74, 2.91 Hz, 1H), 6.81 (td, J=8.46, 2.78 Hz, 1 H), 3.83 (s, 3 H ), 3.72 (s, 3 H), 3.57 (s, 3 H).

[0285] Step 2: 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-meth Synthesis of hydroxy-pyridine-3-carboxylic acid [ka] 5-Fluoro-2-(4-fluoro-2-methyl-2-methylpropional) in THF (3 mL) and water (0.1 mL) (231 mg, 0.710 mmol) and lithium hydroxide monohydrate (32.8 mg, 0.781 mmol The mixture was stirred at room temperature for 48 hours. The solvent was removed under a stream of N2 and the contents were diluted with water (15 The contents were filtered and the pH of the filtrate was adjusted to pH 4 by careful addition of 2N HCl. After stirring for 1 hour, the precipitate was collected by filtration, washed with water, dried in vacuo, and diluted with 5-fluro Oro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-pyridine-3 -carboxylic acid (201 mg, 0.646 mmol, 90.9% yield) was obtained as a white solid. Ta. MS, ES+ m / z 312.0 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 13.05 (br. s ., 1 H), 8.08 (d, J=10.11 Hz, 1 H), 7.17 (dd, J=8.84, 6.06 Hz, 1 H), 7.08 (dd, J =10.74, 2.91 Hz, 1 H), 6.80 (td, J=8.53, 2.91 Hz, 1 H), 3.72 (s, 3 H), 3.56 (s, 3 H).

[0286] Step 3: 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-meth Synthesis of hydroxy-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka] 5-Fluoro-2-(4-fluoro-2-methoxy-phenoxy)propanol in chloroform (2 mL) (oxy)-6-methoxy-pyridine-3-carboxylic acid (40 mg, 0.129 mmol), 3-Methylsulfonylaniline (24.2 mg, 0.141 mmol), HBTU (53 0.6 mg, 0.141 mmol) and DIPEA (56.0 μL, 0.321 mmol) The mixture was stirred at room temperature for 22 hours, and the reaction was only about 25% complete by LCMS. The mixture was stirred at 50° C. for 54 hours. The solvent was removed under a stream of N2, and the residue was dissolved in water / MeOH (3:1 The mixture was sonicated briefly and then stirred at room temperature for 24 hours. The precipitate was collected by filtration, washed with water, dried in vacuo, and purified to give 5-fluoro-2-(4-fluoro- (2-methoxy-phenoxy)-6-methoxy-N-(3-methylsulfonylphenyl) (I)pyridine-3-carboxamide (45.8 mg, 0.0986 mmol, yield 76. 7%) as a white solid. MS, ES+ m / z 465.1 [M+H]+. 1H-NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1 H), 8.38 (s, 1 H), 8.14 (d, J=9.85 Hz, 1 H), 7.99 (d, J=7.07 Hz, 1 H), 7.63 - 7 .70 (m, 2 H), 7.39 - 7.44 (m, 1 H), 7.11 (dd, J=10.74, 2.65 Hz, 1 H), 6.85 (td, J=8.59, 2.78 Hz, 1 H), 3.75 (s, 3 H), 3. 64 (s, 3 H), 3.22 (s, 3 H).

[0287] Example 179: 5-(difluoromethoxy)-2-(4-fluoro-2-methoxy- (phenoxy)-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka]

[0288] Step 1: Synthesis of 3-bromo-2-chloro-5-(difluoromethoxy)pyridine [ka] Add 5-bromo-6-chloro-pyridin-3-ol (1 0.0 g, 4.8 mmol), followed by acetonitrile (20 mL) and water (20 mL Solid potassium hydroxide (5.4 g, 96 mmol) was added and the mixture was dried. The mixture was cooled in a chair / acetone bath. When the mixture began to freeze, 1-[[bromo(difluoromethyl) b) Methyl]-ethoxy-phosphoryl]oxyethane (2.6 g, 9.6 mmol) was added. The crude mixture was partitioned between water and diethyl ether and The ether layer was collected, dried, and concentrated to give a colorless oil containing the desired product, which was further purified. It was used without

[0289] Step 2: Synthesis of 3-bromo-2-chloro-5-(difluoromethoxy)pyridine [ka] The crude product from step 1 (1.2 g, 4.6 mmol) was placed in a round-bottom flask equipped with a magnetic stir bar. ) was added and dissolved in acetonitrile (20 mL). phenol (726 mg, 5.11 mmol) and cesium carbonate (1.7 g, 5.1 mmol) l) was added and the mixture was heated at 60°C for 24 hours. After cooling to room temperature, the crude mixture The mixture was diluted with water and extracted with dichloromethane. The combined organic layers were dried, concentrated, and then evaporated on silica gel. Purification by chromatography (0-35% EtOAc in heptane) afforded the desired product as a colorless as an oil which solidified on standing (1.1 g, 3.1 mmol). MS, ES+ m / z 364.0 / 365.0 [M+H]+.

[0290] Step 3: 5-(difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy) Synthesis of β-N-(3-methylsulfonylphenyl)pyridine-3-carboxamide [ka] In a microwave vial equipped with a magnetic stir bar, add 3-bromo-5-(difluoromethoxy)- 2-(4-fluoro-2-methoxy-phenoxy)pyridine (250 mg, 0.69 mm ol), DPEPhos (27.7 mg, 0.05 mmol), palladium acetate (II ) (3.85 mg, 0.02 mmol), 3-methylsulfonylaniline (235 mg, 1.37 mmol) and cesium hydroxide (1.2 g, 6.9 mmol) were added. The tube was sealed, evacuated and backflushed with nitrogen three times, and then toluene (4 mL) and chloroform were added. (0.17 mL) was added. The resulting mixture was heated at 80°C for 18 hours and cooled to room temperature. Afterwards, it was diluted with dichloromethane and filtered through a plug of Celite. The clear filtrate was concentrated and Purification by preparative reverse phase HPLC (high pH method) gave the desired product as a colorless solid (166 mg, yield 50.1%). MS, ES+ m / z 483.0 [M+H]+. 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.18 - 3. 26 (m, 3 H) 3.68 - 3.72 (m, 3 H) 6.83 (t d, J=8.53, 2.91 Hz, 1 H) 7.06 - 7.11 (m, 1 H) 7.32 (dd, J=8.72, 5.94 Hz, 1 H) 7. 64 - 7.73 (m, 2 H) 7.93 - 8.02 (m, 1 H) 8.07 (d, J=3.03 Hz, 1 H) 8.16 (d, J=2.78 Hz, 1H) 8.41 (s, 1H) 10.90 (s, 1H)

[0291] Example 180: N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trimethylphenyl)-2-(methylsulfonylphenyl)-2-(trimethyl ... (trifluoromethoxy)phenoxy]pyridine-3-carboxamide [ka]

[0292] Step 1: 2-chloro-N-(3-methylsulfonylphenyl)-5-nitro-pyridine Synthesis of α-3-carboxamide [ka] 2-Chloro-5-nitro-pyridine-3-carboxylic acid in dichloromethane (200 mL) (10 g, 49.37 mmol) was added to a stirred solution of oxalyl chloride (6.35 mL, 74. DMF (g, 2.47 mmol) (3 drops) was added. The solution was stirred at room temperature for 5 hours until no more bubbles were observed coming out of the solution. N,N-diisopropyl aniline (10.14 g, 59.24 mmol) was added. Ethylamine (17.72 mL, 98.74 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 1 hour. DCM (200 mL) was added and the solution was diluted with hydrochloric acid solution (1N, 2×100 The solution was extracted with brine (100 mL) and then dried over sodium sulfate. The residue was extracted with ethyl acetate / heptane (30-100% gradient). Purify by silica gel chromatography eluting with 2-chloro-N-(3-methylsulfonyl) (5-nitro-2-phenylphenyl)-5-nitro-pyridine-3-carboxamide (11.28g, 22.1 95 mmol, 44.957% yield) was obtained as a purple solid. MS, ES+ m / z 356.0 [M+H]+. 1H NMR (400 MHz, chloroform- d) δ ppm 3.02 - 3.11 (m, 3 H) 7.60 - 7.8 2 (m, 3 H) 7.94 - 8.05 (m, 1 H) 8.61 (d, J=2.78 Hz, 1 H) 9.22 - 9.31(m, 1 H).

[0293] Step 2: N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethyl)phenyl]-2-methyl- Synthesis of (2-(4-methoxy)phenoxy)pyridine-3-carboxamide [ka] 2-Chloro-N-(3-methylsulfonylphenyl) in acetonitrile (100 mL) A stirred solution of 5-nitro-pyridine-3-carboxamide (11.18 g, 22 mmol) The solution was added with 4-(trifluoromethoxy)phenol (5.88 g, 33 mmol) and carbonate. Potassium (6.08 g, 44 mmol) was added, and the solution was stirred at 60°C overnight. The mixture was cooled to room temperature and filtered to remove solids. Water (300 mL) was added. The colored solid was isolated by filtration and dried to give N-(3-methylsulfonylphenyl)- 5-Nitro-2-[4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide The slightly colored amide (10.43 g, 20.969 mmol, 95.32% yield) A small sample of 100 mg was extracted with ethyl acetate / heptane (0-60%). Purified by ISCO and eluted N-(3-methylsulfonylphenyl)-5-nitro-2- [4-(trifluoromethoxy)phenoxy]pyridine-3-carboxamide (10.4 3 g, 20.97 mmol, 95.32% yield) was obtained as a white solid. MS, ES+ m / z 498.0 [M+H]+. 1H NMR (400 MHz, chloro Form-d) d ppm 3.12 (s, 3 H) 7.26 - 7.38 ( m, 3 H) 7.43 (d, J=8.84 Hz, 2 H) 7.61 - 7.70 (m, 1 H) 7.79 (dd, J=7.83, 1.26 Hz, 1 H) 8.10 - 8.21 (m, 2 H) 9.12 (d, J=2. 78 Hz, 1 H) 9.48 (d, J=2.78 Hz, 1 H) 9.6 8 (s, 1 H).(m, 1 H).

[0294] Example 181: 5-chloro-N-(3-methylsulfonylphenyl)-2-[4-(trimethylphenyl)-2-(methylsulfonyl)phenyl]-2-(4-methylphenyl)-2-(tri ... (trifluoromethoxy)phenoxy]pyridine-3-carboxamide [ka]

[0295] Step 1: 5-amino-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethyl)phenyl]-2-methyl- Synthesis of (2-(4-methoxy)phenoxy)pyridine-3-carboxamide [ka] N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethacrylamide) [Ci)phenoxy]pyridine-3-carboxamide (10.33g, 20.77mmol) In a stirred solution of 1,2-dichloro- ... 0% (g, 20.77 mmol) was added. Nitrogen was bubbled through the solution for 5 minutes. The solution was filled with a hydrogen balloon and stirred for 2 days. The solution was filtered and concentrated. The residue was dissolved in methanol. Purified by ISCO eluting with methanol / DCM (0-8%) and 5-amino-N-(3-methyl- Sulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy]pyridine-3 -carboxamide (4.64 g, 9.9268 mmol, 47.799% yield) as a white solid The compound was obtained as a methyl group. MS, ES+ m / z 468.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 3.15 - 3.26 (m , 3 H) 5.44 (s, 2 H) 7.12 - 7.21 (m, 2 H ) 7.30 - 7.41 (m, 3 H) 7.60 - 7.71 (m, 3 H) 7.92 (d, J=7.58 Hz, 1 H) 8.38 (s, 1 H) 10.76 (s, 1 H).

[0296] Step 2: 5-chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethyl)phenyl]-2-methyl- Synthesis of (2-(4-methoxy)phenoxy)pyridine-3-carboxamide 5-Amino-N-(3-methylsulfonylphenyl)-2-[4-(trimethylphenyl)-2-(2-methyl-2-propanol]-2-yl]propanol] in water (3 mL) (trifluoromethoxy)phenoxy]pyridine-3-carboxamide (200 mg, 0.4 To a stirred solution of 300 mmol of HCl was added 2 mL of hydrochloric acid. The solution was cooled in an ice-water bath and diluted with water ( Sodium nitrite (32.48 mg, 0.4700 mmol) dissolved in 0.2 mL of After stirring at 0°C for 15 minutes, copper(II) chloride (172.5 mL) dissolved in water (1 mL) was added. 9 mg, 1.28 mmol) was added to the solution, which was stirred at room temperature overnight. The combined organic solution was extracted with water (2 mL), brine (2 mL). The solution was filtered and concentrated. The residue was dissolved in ethyl acetate / Purified by ISCO eluting with heptane (0-50%) and 5-chloro-N-(3-methylsulfonyl) (4-(trifluoromethoxy)phenoxy)pyridine-3- The carboxamide (43 mg, 0.0883 mmol, 20.642% yield) was obtained as a white solid. MS, ES+ m / z 487.0 [M+H]+. 1H NMR ( 400 MHz, CHLOROFORM-d) d ppm 3.11 (s, 3 H) 7.24 - 7.32 (m, 2 H) 7.39 (d, J=8.34 Hz, 2 H) 7.58 - 7.68 (m, 1 H) 7.74 - 7.8 3 (m, 1 H) 8.10 (d, J=8.08 Hz, 1 H) 8.17 (t, J=1.89 Hz, 1 H) 8.23 ​​(d, J=2.53 Hz, 1 H) 8.70 (d, J=2.53 Hz, 1 H) 9.79 (s, 1 H).

[0297] (Assay Method) Ability of the pyridine carboxamide derivatives exemplified above to inhibit Nav1.8 channels was measured using one or more of the methods described below.

[0298] (HEK Nav1.8 β1 / β2 stable expressing cell line) Human Nav1.8 (hNav1.8) ion channel with β1 / β2 subunits We constructed a HEK293 cell line stably expressing α-glucanase (α-glucanase) and α-glucanase (α-glucanase) in vitro. This cell line was used for fluorescence and electrophysiological studies. IC in a cytochrome P450-based assay 50 It is also suitable for measuring the mechanism of action in electrophysiological assays. It is also suitable for conducting pharmacological studies. The monolayer was treated with the selective agents G418 (400 mg / L) and puromycin (0.5 mg / L ) containing DMEM / high glucose medium, 10% fetal bovine serum, and sodium pyruvate (2 mM) , Hepes (10 mM), and cultured at 37°C and 10% CO2.

[0299] (Nav1.8 fluorescence inhibition assay) Compounds were prepared as 10-mM stock solutions in DMSO or as 10- Concentration-response curves were performed using a Matrix multichannel pipette. The compound source plate was prepared using a petter. Dilute to make a 500 μM (100x) solution in DMSO in a 96-well V-bottom plate The compound was then serially diluted with 100% DMSO, and 5-point, 4-fold dilutions were performed. A dose-response curve was then created for each of the 2 μL 100-fold dose-response curves. Then, 100 μL of pre-incubation medium was added to the assay plate. Add 200 μL of ion buffer and 200 μL of stimulation buffer to the plate to obtain the final assay test concentrations. The range was 5 μM to 0.02 μM, and the final DMSO concentration was 1%.

[0300] On the day of the assay, add 2K EBSS buffer (135 mM NaCl, 2 mM KCl, 5 mM 2 mM glucose, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4) to wash the plate and remove the cell culture medium. Incubate Asante Natrium Green-2 (ANG-2) for 60 minutes After equilibrating with EBSS, the plate is washed with 2K EBSS. FLIPR TM (Molecular Devices) and an excitation wavelength of 490 nm. Fluorescence measurements were performed using an emission wavelength of 565 nm. ) at the final test concentration for 5 min, and then mediated by the Na+ / K+ exchanger. Inhibits Na+ efflux. Following the preincubation step, 10 μM pyrethroid The methionine derivative deltamethrin stimulates the hNav1.8 channel and prevents channel inactivation. The assay was run for 15 min using 30 μM of tetracaine and 30 μM of tetracaine as negative and positive controls, respectively. The peak changes in fluorescence for the negative and positive control wells were calculated and analyzed using a logistic regression. By fitting the equation 50 It was decided that:

[0301] (Na by PatchXpress v 1.8 Inhibition Assay HEK-Nav1.8 β1 / β2 cells were analyzed using PatchXpress automated patch-clone technology. Whole cell cytoplasmic transfer was performed using a cytoplasmic transfer platform (Molecular Devices). Cell suspensions were prepared after trypsinization of the attached monolayers for a minimum of 3 min. The compounds were prepared from 10 mM DMSO stocks. It was prepared from the following:

number

[0302] Mutant forms of the Nav1.8 channel were evaluated using protocol 1. First, cells were voltage-clamped at a holding potential of -100 mV to maintain Nav1.8 in a closed, resting state. After the amplitude of the current stabilized, the current was gradually increased to depolarizing voltages (-100 to 0 mV). Use a series of 5-second adjustment steps to determine the steady-state inactivation midpoint voltage for each cell. The holding potential was then set to the voltage at which approximately 50% of the cells were inactivated (V 半分 -PatchX Press to reset the closed and inactivated channels (automatically set by the script). Protocol 1 allows for the evaluation of the inhibition of the current. The frequency was 0.1 Hz (determined automatically by the PatchXpress script). The effect of test reagents on NaV current amplitude was measured after compound addition and washout. Monitor using custom PatchXpress stability scripts to determine timing -I did.

[0303] DataXpress 2.0 (Molecular Devices) was used to The data was processed and analyzed. The inhibition rate was calculated using the formula: % inhibition = ((control + washout) / 2 )-drug) / ((control+washout) / 2)*100 (see schematic above) Mic was used so that compound inhibition was normalized to the mean of the control and washout currents. Calculations were performed using rosoft Excel. Normalized concentration-response relationships were calculated using XLfit Four-parameter logistic model or sigmoidal dose-response model in software (IDBS) The model was used to fit.

[0304] (hNa V 1.8 Automated Patch Clamp - IonFlux HT Assay) For recording inward sodium currents, we used the IonFlux HT automated whole-cell patch-clamp system. Fluxion Biosciences, Alameda, CA, USA ) was used.

[0305] HEK-293 cells were transfected with human NaV1.8 cDNA (X-type voltage-gated sodium Channel α subunit, accession number NM_006514) and human β subunit The cells were stably transfected with WT1 (accession number NM_001037). Cells were harvested with liposomal lipase and maintained at room temperature in serum-free medium before recording. It was resuspended in solution and then loaded into the device.

[0306] Test concentration: Stock solution was prepared in DMSO at 300x the final assay concentration and used in the assay. The stock solution was stored at -80°C until the day of assay. On the day of assay, an aliquot of the stock solution was thawed and The final test concentrations were obtained by diluting the assay compounds and controls in 0.33% water. The final concentration of DMSO was maintained.

[0307] Recording conditions: Intracellular solution (mM): 100 CsF, 45 CsCl, 5 NaCl, 1 0 HEPES, 5 EGTA (pH 7.3, titrated with 1M CsOH).

[0308] Extracellular solution (mM): 150 NaCl, 4 BaCl, 1 MgCl2, 1.8 C aCl2, 10 HEPES, 5 glucose, (pH 7.4, titrated with 10 M NaOH) ).

[0309] When sodium channels are held at a depolarized membrane potential, the channels open and become inactivated. The inactivated channels remain inactivated until the membrane potential returns to a hyperpolarized membrane potential and the inactivated channels are restored to a closed state. Compounds that show greater inhibition in pulse 2 compared to pulse 1 are state-dependent. An example is tetracaine, which is a potent inhibitor of the inactivated state rather than the tense or open state. It is a more potent inhibitor.

[0310] The cell was held at -120 mV for 50 ms and then stepped to -10 mV over 2 s. Pulse 1 was applied to fully inactivate sodium channels (pulse 2), followed by a voltage of −120 mV for 10 ms. (fully recovers from inactivation, but inhibitor-bound channels recover from inactivation) (may not recover), then stepped to -10 mV for 50 ms (pulse 2). The interval was 20 seconds (0.05 Hz). Each concentration of compound was applied for 2 minutes. I went with warm.

[0311] Reference compound: Tetracaine was used as a positive control and tested simultaneously with the test compounds.

[0312] Data analysis: Only current amplitudes above 3 nA during the reference phase were analyzed. The width is the peak inward current (i.e., the peak The sodium current was calculated by measuring the difference between the current at the end of the step and the remaining current at the end of the step. was assessed in vehicle control conditions and then at the end of each 2-minute compound application. Trap results were normalized to the amplitude of the vehicle control and shown as mean ± SEM for each compound concentration. These values ​​were then plotted to give an estimated IC 50 A curve fit was calculated.

[0313] Estimated IC of the pyridine carboxamide compounds exemplified above 50 The values ​​are shown in Table 1. [Table 21-1] [Table 21-2] [Table 21-3]

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Carboxamide Derivatization by Yao et al., published June 26, 2018 U.S. Patent No. 10,005,768 for ives and Use Thereof ; Therapeutic Comp by Andrez et al., published June 26, 2018 US Patents on Methods and Methods of Use Thereof No. 10,005,724; Triazine Carboxylate by Tadesse et al., published June 19, 2018 US Patent on amides as Sodium Channel Blockers Permit No. 10,000,475; Published on May 15, 2018 by Bogdan et al. or 6-aryloxy-quinoline-2-Carboxamides a nd Method of Use, U.S. Patent No. 9,969,693; Prodrugs of P by Anderson et al., published November 28, 2017 yridone Amides Useful as Modulators of S U.S. Patent No. 9,828,397 for sodium Channels; Substitute by Hadida-Ruah et al., published October 10, 2017 d Quinolines as Modulators of Sodium Cha U.S. Patent No. 9,783,501 relating to nnels; Bicylic Derivati ​​by Termin et al., published September 17, 2013 ves as Modulators of Voltage Gated Ion C U.S. Patent No. 8,536,195 relating to hannels; Bicylic Deriva by Kawatkar et al., published on July 23, 2013 tives as Modulators of Voltage Gated Ion U.S. Patent No. 8,492,403 relating to Channels; Bicyclic Deriva by Termin et al., published November 20, 2012 tives as Modulators of Ion Channels National Patent No. 8,314,125; Compositions by Gonzalez et al., published November 13, 2012 Useful as Inhibitors of Voltage-Gated So U.S. Patent No. 8,309,543 for dium Channels; Biphenyl D by Martinborough et al., published on August 7, 2012 erivatives as Modulators of Voltage Gate d U.S. Patent No. 8,236,833 for Ion Channels; Bicyclic Derivatization by Neubert et al., published August 7, 2012 ives as Modulators of Voltage Gated ION U.S. Patent No. 8,236,829 relating to Channels; Indane Derivativ by Neubert et al., published August 2, 2011 es as Modulators of Sodium Channels National Patent No. 7,989,481; Benzimidazoles U by Wilson et al., published April 28, 2010 secure as Modulators of Ion Channels National Patent No. 7,705,031. Carboxamides as M by Ahmad et al., published on January 17, 2019 Published U.S. Patent Application for Sodium Channel Modulators No. 2019 / 0016671 A1.

[0315] The foregoing subject matter has been described in some detail by way of illustrations and examples for purposes of clarity of understanding. However, it will be apparent to those skilled in the art that certain changes and modifications may be practiced within the scope of the appended claims. You will understand what you will get.

Claims

1. Compounds of formula (I): 【Chemistry 1】 [In the formula, X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R １ is aryl or heteroaryl, and the aryl or heteroaryl is unsubstituted or is selected from mono-, di- and trihalo-C １ -C ４ Alkyl, substituted or unsubstituted is unsubstituted C １ -C ８ Alkyl, C ３ -C １０ Cycloalkyl, halogen, heteroaryl , cyano, amino, nitro, aryloxyl, aryl, C １ -C ８ Alkoxyl, molybdenum No-, di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfa substituted with one or more groups selected from the group consisting of aryl, arylalkoxy, and arylalkoxy; It has been; R ２ is selected from the group consisting of aryl, heteroaryl, and heterocycle, The heteroaryl and heterocycles are unsubstituted or include mono-, di- and trihalo-C １ - C ４ Alkyl, substituted or unsubstituted C １ -C ８ Alkyl, C ３ -C １０ cycloalkyl, Halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C １ -C ８ Alkoxyl, mono-, di- or trihaloalkoxyl, arylalkoxy Sil, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfano alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl substituted with one or more groups selected from the group R ３ When Y is carbon, hydrogen, cyano, halogen, C １ -C ８ Alkoxyl, mono-, Di- and trihalo-C １ -C ４ Alkyl, mono-, di- and trihalo-C １ -C ４ Arco xyl, substituted or unsubstituted C １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, —NO ２ from and absent when Y is nitrogen; R ４ is hydrogen, cyano, halogen, C １ -C ８ Alkoxy, mono-, di- and trihalo -C １ -C ４ Alkyl, mono-, di- and trihalo-C １ -C ４ Alkoxy, substituted or or unsubstituted C １ -C ８ alkyl and morpholinyl, wherein R ３ Reach BiR ４ is not also hydrogen; or R ３ and R ４ Together, R ３ and R ４ C including the carbon atom to which ３ -C ５ forming a carbocyclic ring]; and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1, wherein X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R １ is phenyl or pyridinyl, and said phenyl or pyridinyl is a non-substituted or substituted or unsubstituted C １ -C ８ Alkyl, halogen, —O—R ５ (In the ceremony , R ５ is C １ -C ８ Alkyl, —CF ３ , -CHF ２ and -(CH ２ ) ｐ -CF ３ (formula wherein p is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8; and —S—CF ３ One or more selected from the group consisting of is substituted with a number of groups; R ２ is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, pyridine-1 -oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl and 1,3-benzoxylidene phenyl, pyridyl, pyrimidinyl, pyridyl, thiazolyl; diphenyl, pyridine-1-oxide, 1,2,3-thiadiazolyl, 1,2,4-triazolyl aryl and 1,3-benzothiazolyl are unsubstituted or unsubstituted or substituted C １ - C ８ Alkyl, halogen, cyano, oxo, -O-R ５ (In the formula, R ５ is C １ -C ８ Al Kill, -CF ３ and -CHF ２ -(CH ２ ) ｑ -OH (formula wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ alkyl (can be used as a divalent metal ion), morpholinyl, oxazolyl, -C(=O)-R ８ (In the formula, R ８ is -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ alkyl) and C １ -C ４ alkyl), —S(═O)—R ９ , -S(=O) ２ -R ９ , -S(=O)(=NR １０ )-R １１ and -N=S(=O)-(R １１ ) ２ ( In the formula, each R ９ are independently １ -C ４ Alkyl, —CF ３ or -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ alkyl), and R １０ teeth H or C １ -C ４ alkyl, and R １１ is C １ -C ４ alkyl) and substituted with one or more groups selected from the group consisting of: Y is nitrogen and R ２ is phenyl or In the case of pyridyl, R ８ -NR ６ R ７ provided that: R ３ When Y is carbon, hydrogen, cyano, halogen, -CF ３ , C １ -C ８ Arco Xyl, —O—CH(F) ２ , substituted or unsubstituted C １ -C ８ Alkyl, C ３ -C ８ Cycloa Rukill, -N ＋ (=O)-O － and absent when Y is nitrogen; R ４ is hydrogen, cyano, halogen, C １ -C ８ Alkoxyl, -CF ３ , substituted or unsubstituted C １ -C ８ alkyl, and morpholinyl, wherein R ３ and R ４ The same provided that it is sometimes not hydrogen; or R ３ and R ４ Together, R ３ and R ４ C including the carbon atom to which ３ -C ５ forming a carbocyclic ring]; and pharmaceutically acceptable salts thereof.

3. 10. The compound of claim 1 having the structure: 【Chemistry 2】 [In the formula, X is —CH— or nitrogen; Y is carbon or nitrogen, provided that at least one of X and Y is nitrogen; R ２ is selected from the group consisting of aryl, heteroaryl, and heterocycle, The heteroaryl and heterocycles are unsubstituted or include mono-, di- and trihalo-C １ - C ４ Alkyl, substituted or unsubstituted C １ -C ８ Alkyl, C ３ -C １０ cycloalkyl, Halogen, heteroaryl, cyano, amino, nitro, aryloxyl, aryl, C １ -C ８ Alkoxyl, mono-, di- or trihaloalkoxyl, arylalkoxy Sil, oxo, alkylsulfinyl, alkylsulfonyl, alkyliminosulfano alkylsulfoxide, sulfonamide, morpholinyl and oxazolyl substituted with one or more groups selected from the group R ３ When Y is carbon, hydrogen, cyano, halogen, C １ -C ８ Alkoxyl, mono-, Di- and trihalo-C １ -C ４ Alkyl, mono-, di- and trihalo-C １ -C ４ Arco xyl, substituted or unsubstituted C １ -C ８ Alkyl, C ３ -C ８ Cycloalkyl, —NO ２ from and absent when Y is nitrogen; R ４ is hydrogen, cyano, halogen, C １ -C ８ Alkoxy, mono-, di- and trihalo -C １ -C ４ Alkyl, mono-, di- and trihalo-C １ -C ４ Alkoxy, substituted or or unsubstituted C １ -C ８ alkyl and morpholinyl, wherein R ３ Reach BiR ４ is not also hydrogen; or R ３ and R ４ Together, R ３ and R ４ C including the carbon atom to which ３ -C ５ forming a carbocyclic ring; n is an integer selected from 0, 1, 2, 3, 4 and 5; Each R ２４ are independently mono-, di- and trihalo-C １ -C ４ Alkyl, substituted or unsubstituted Exchange C １ -C ８ Alkyl, C ３ -C １０ Cycloalkyl, halogen, heteroaryl, cyano No, amino, nitro, aryloxyl, aryl, C １ -C ８ Alkoxyl, mono-, Di- or trihaloalkoxyl, sulfanyl, trifluoromethylsulfanyl and arylalkoxyl; and pharmaceutically acceptable salts thereof.

4. R ２ The compound of claim 4, wherein is selected from the group consisting of: 【Transformation 3】 [In the formula, m is an integer selected from the group consisting of 0, 1, 2, 3, and 4; R ２５ is H, morpholinyl, oxazolyl, halogen, cyano, -(CH ２ ) ｑ -OH wherein q is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, and 8. , —C(═O)—R ８ (In the formula, R ８ is -NR ６ R ７ and C １ -C ４ alkyl R ６ and R ７ is H and C １ -C ４ alkyl) , -S(=O)-R ９ , -S(=O) ２ -R ９ , -S(=O)(=NR １０ )-R １１ and and -N=S(=O)-(R １１ ) ２ (In the formula, each R ９ are independently １ -C ４ Alkyl , -CF ３ or -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ From alkyl is selected from the group consisting of １０ is H or C １ -C ４ alkyl, and R １１ is C １ -C ４ alkyl), wherein Y is nitrogen and R ２ is phenyl or In the case of pyridyl, R ８ -NR ６ R ７ provided that: R ２６ is halogen or cyano; Each R ２７ are independently H, halogen, C １ -C ８ Alkoxyl, cyano and -NR ６ R ７ selected from the group consisting of: Each R ２８ are independently H or C １ -C ４ alkyl].

5. The compound of claim 1, wherein the compound of formula (I) is a compound of formula (IF): 【Chemistry 4】 [In the formula, R ２ is selected from the group consisting of aryl and heteroaryl, Aryl is optionally substituted with cyano, heterocycloalkyl, -S(=O)-R ９ , -S( =O) ２ -R ９ , -S(=O)(=NR １０ )-R １１ and -N=S(=O)-(R １ １ ) ２ (In the formula, each R ９ are independently １ -C ４ Alkyl, —CF ３ or -NR ６ R ７ ( In the formula, R ６ and R ７ is H and C １ -C ４ alkyl), R １０ is H or C １ -C ４ alkyl, and R １１ is C １ -C ４ (It is alkyl) substituted with a substituent selected from the group consisting of: R １２ is a halogen; R １３ is C １ -C ４ alkyl].

6. The aryl and heteroaryl are phenyl, benzothiazolyl, pyridyl, pyridyl and pyrimidinyl, each of which is optionally selected from the group consisting of silyl N-oxide and pyrimidinyl. Ano, heterocycloalkyl, —S(═O)—R ９ , -S(=O) ２ -R ９ , -S(=O ) (=NR １０ )-R １１ and -N=S(=O)-(R １１ ) ２ (In the formula, each R ９ is German Stand up, C １ -C ４ Alkyl, —CF ３ or -NR ６ R ７ (In the formula, R ６ and R ７ H and Bi C １ -C ４ alkyl), and R １０ is H or C １ -C ４ a It is Rukill and R １１ is C １ -C ４ and a substituent selected from the group consisting of: is substituted; R １２ is fluorine; R １３ The compound of claim 5 , wherein is methyl.

7. R ２ 1,3-benzothiazol-6-yl, 3-morpholinophenyl, 3-cyano Phenyl, 4-cyanophenyl, 3-pyridyl, 4-pyridyl, 6-cyano-3-pyridyl 3-methylsulfinylphenyl, 3-oxazol-5-ylphenyl, 3-dimethylphenyl Thilsulfamoylphenyl, 1,3-benzothiazol-2-yl, pyrimidin-4- yl, (trifluorosulfonyl)phenyl, 3-(methylsulfonimidoyl)phenyl 2-Methoxy-4-pyridyl, 3-(N,S-dimethylsulfonimidoyl)phenyl 2-methyl-4-pyridyl, 6-methyl-3-pyridyl, pyridazin-4-yl and Dimethyl(oxo)-λ ６ -sulfanylidene]amino]phenyl The compound of claim 6.

8. The compound of claim 1, wherein the compound is a compound of formula (IG): 【Transformation 5】 [In the formula, R １ is C １ -C ８ Alkyl, halogen and C １ -C ８ one or more of the alkoxyl is a phenyl substituted with a number of C １ -C ８ The alkoxyl may optionally be one or is substituted with multiple halogens; R １４ is C １ -C ４ alkyl].

9. The R １ However, 2,4-dichlorophenyl, 2,4-dimethylphenyl, 2-chloro-4 -methoxyphenyl, 2-propylphenyl, 2-methoxy-4-methylphenyl, 2- Methoxy-4-chlorophenyl, 2-isopropoxyphenyl, 4-difluoromethoxy Phenyl, 2,4-dimethoxyphenyl, 2-chloro-4-methoxyphenyl, 3,4- selected from the group consisting of difluorophenyl and 2-chloro-4-fluorophenyl; The compound of claim 8.

10. The compound of claim 1, wherein the compound is a compound of formula (I-H-i): 【Transformation 6】 [In the formula, R １ is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4yl wherein the phenyl and pyridyl may be unsubstituted or may be substituted with halogen, C １ -C ８ Al Kill, -O-R ５ (In the formula, R ５ is C １ -C ８ Alkyl, —CF ３ , -CHF ２ and -( CH ２ ) ｐ -CF ３ (wherein p is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8) -S-CF ３ , -NR ６ R ７ (In the ceremony , R ６ and R ７ is H and C １ -C ４ alkyl) may be replaced by a number; R ３ and R ４ is H or -CF ３ However, R ３ If H, then R ４ Ha-CF ３ and R ４ If H, then R ３ Ha-CF ３ provided that: R １４ is C １ -C ４ is alkyl; R １５ is O or NR １０ (In the formula, R １０ is H or C １ -C ４ alkyl) ］。

11. R １ phenyl, 4-fluorophenyl, 4-fluoro-2-methoxyphenyl, 2 -chloro-4-fluorophenyl, 2-methyl-4-trifluoromethoxyphenyl, 4 -trifluoromethoxyphenyl, difluoromethoxyphenyl, 3-fluoro-4-thiazolinone trifluoromethoxyphenyl, 3-fluorophenyl, 2,5-difluorophenyl, 4 -methylphenyl, 3-chloro-5-fluorophenyl, 2-isopropylphenyl, 3, 4-difluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 4-(2,2,2-trifluoroethoxy)phenyl, 4-(trifluoromethylsulfonyl) phenyl, 2-dimethylaminophenyl, 2-trifluoromethylphenyl, 2, 4-dimethoxyphenyl, 3,4,5-trifluorophenyl, 3,5-dichlorophenyl 6-trifluoromethyl-3-pyridyl, 1,3-benzothiazol-4-yl, 4 -difluoromethoxyphenyl, 2-chloro-4-fluorophenyl, 2-chloro-4- 11. The compound according to claim 10, wherein the aryl group is selected from the group consisting of methoxyphenyl and 2-chlorophenyl. Compound.

12. The compound of claim 1, wherein the compound is a compound of formula (I-H-ii): 【Transformation 7】 [In the formula, R １ is selected from the group consisting of phenyl, pyridyl and 1,3-benzothiazol-4yl wherein the phenyl and pyridyl may be unsubstituted or may be substituted with halogen, C １ -C ８ Al Kill, -O-R ５ (In the formula, R ５ is C １ -C ８ Alkyl, —CF ３ , -CHF ２ and -( CH ２ ) ｐ -CF ３ (wherein p is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7 and 8) -S-CF ３ , -NR ６ R ７ (In the ceremony , R ６ and R ７ is H and C １ -C ４ alkyl) may be replaced by a number; R ３ and R ４ is H or -CF ３ However, R ３ If H, then R ４ Ha-CF ３ and R ４ If H, then R ３ Ha-CF ３ subject to the condition that

13. R １ 2,4-dichlorophenyl, 4-difluoromethoxyphenyl and 2-chlorophenyl 13. The compound of claim 12, wherein the compound is selected from the group consisting of: -4-methoxyphenyl.

14. The compound of claim 1, wherein the compound is a compound of formula (II): 【Transformation 8】 [In the formula, R ２ is selected from the group consisting of phenyl, pyridazinyl and pyridyl, said phenyl being , halogen, —S(═O)—R ９ , -S(=O) ２ -R ９ and -S(=O)(=NR １０ )-R １１ (In the formula, each R ９ are independently １ -C ４ Alkyl, —CF ３ or -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ alkyl) Ri, R １０ is H or C １ -C ４ alkyl, and R １１ is C １ -C ４ alkyl) may be substituted with one or more; R １６ is a halogen; R １７ is C １ -C ４ alkyl].

15. R ２ 3-methylsulfinylphenyl, 2-fluoro-5-methylsulfonylphenyl phenyl, 3-(N,S-dimethylsulfonimidoyl)phenyl, pyridazinyl and pyridinyl 15. The compound of claim 14, selected from the group consisting of:

16. The compound of claim 1, wherein the compound is a compound of formula (I-J): 【Chemistry 9】 [In the formula, R ２ is selected from the group consisting of phenyl and pyridyl, wherein said phenyl is selected from the group consisting of halogen, - C(=O)-R ８ (In the formula, R ８ is -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ - C ４ alkyl) and C １ -C ４ alkyl (=O)-R ９ , -S(=O) ２ -R ９ , -S(=O)(=NR １０ )-R １１ and -N=S(=O)-(R １１ ) ２ (In the formula, each R ９ are independently １ -C ４ a Rukill, -CF ３ or -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ Alkyl and R １０ is H or C １ -C ４ alkyl, and R １１ is C １ -C ４ alkyl); R １８ is a halogen].

17. R ２ 3-methylsulfonylphenyl, 3-methylsulfinylphenyl, 3-(diphenyl 2-fluoro-5-methylsulfonylphenyl, 3- (methylsulfonimidoyl)phenyl, 3-carbamoylphenyl, 3(N,S-dimethylphenyl) Selected from the group consisting of (phenylsulfonimidoyl)phenyl, 3-pyridyl and 4-pyridyl 17. The compound of claim 16,

18. The compound of claim 1, wherein the compound is a compound of formula (I-K): 【Chemistry 10】 [In the formula, R １ is a halogen, C １ -C ８ Alkyl, —O—R ５ (In the formula, R ５ is C １ -C ８ Archi Ru, -CF ３ , -CHF ２ and -(CH ２ ) ｐ -CF ３ (wherein p is 1, 2, 3, 4, 5, 6, 7, and 8). and one or more substituted phenyl.

19. R １ 4-fluoro-2-methoxyphenyl, 4-fluoro-2-methylphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 2,4-dimeth The group consisting of 2,4-difluorophenyl, 2,4-difluorophenyl, and 3,4-difluorophenyl 19. The compound of claim 18 selected from:

20. The compound of claim 1, wherein the compound is a compound of formula (IL): 【Chemistry 11】 [In the formula, R ２ is selected from the group consisting of phenyl, pyridyl and pyridazin-4-yl, Phenyl is -S(=O) ２ -R ９ , -S(=O)(=NR １０ )-R １１ and -N=S (=O)-(R １１ ) ２ (In the formula, each R ９ are independently １ -C ４ Alkyl or -NR ６ R ７ (In the formula, R ６ and R ７ are H and R １０ is H or C １ -C ４ It is alkyl Ri, R １１ is C １ -C ４ substituted with alkyl).

21. The compound of claim 1, wherein the compound is a compound of formula (I-M-i): 【Chemistry 12】 [In the formula, R ２ is 3-(N,S-dimethylsulfonimidoyl)phenyl or pyridin-4-yl le; R １６ is a halogen; R １９ is C １ -C ４ alkyl].

22. The compound of claim 1, wherein the compound is a compound of formula (I-M-ii): 【Chemistry 13】 [In the formula, R １ is 4-trifluoromethoxyphenyl, 4-difluoromethoxyphenyl , 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2 , 4-difluorophenyl].

23. The compound of claim 1, wherein the compound is a compound of formula (I-M-iii): 【Chemistry 14】 [In the formula, R １ are 4-difluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2,4-di fluorophenyl; R ２０ is C １ -C ４ is alkyl; R ２１ is H or C １ -C ４ alkyl].

24. The compound of claim 1, wherein the compound is a compound of formula (I-M-iv): 【Chemistry 15】 [In the formula, R １ represents 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl , 2-chloro-4-trifluoromethoxyphenyl, 2,4-dimethoxyphenyl and 2 , 4-difluorophenyl].

25. The compound of claim 1, wherein the compound is a compound of formula (I-N): 【Chemistry 16】 [In the formula, R ２ is 3-(N,S-dimethylsulfonimidoyl)phenyl, 3-(methylsulfon selected from the group consisting of (imidoyl)phenyl and pyridazin-4-yl; R １６ is a halogen; R １９ is C １ -C ４ alkyl].

26. The compound of claim 1, wherein the compound is a compound of formula (IO): 【Chemistry 17】 [In the formula, R ２ is selected from the group consisting of phenyl, pyridyl and pyridazin-4-yl, Phenyl is -S(=O) ２ -R ９ , -S(=O)(=NR １０ )-R １１ and -N=S (=O)-(R １１ ) ２ (In the formula, each R ９ are independently １ -C ４ Alkyl or -NR ６ R ７ (In the formula, R ６ and R ７ are H and R １０ is H or C １ -C ４ It is alkyl Ri, R １１ is C １ -C ４ substituted with alkyl).

27. The compound of claim 1, wherein the compound is a compound of formula (IP): [Chemistry 18] [In the formula, R １ is 4-fluoro-2-methylphenyl, 4-fluoro-2-methoxyphenyl 2,4-difluorophenyl, 4-difluoromethoxyphenyl, 2,4-dimethanyl 2-chloro-4-methoxyphenyl, 3,4-difluorophenyl and 2- chloro-4-fluorophenyl].

28. The compound of claim 1, wherein the compound is a compound of formula (I-Q): 【Chemistry 19】 [In the formula, R ２ are phenyl, pyridyl, pyrazolyl, pyrimidinyl, pyridazinyl, thiadiazolyl selected from the group consisting of pyrazolyl, 1,2,4-triazolyl, Phenyl is unsubstituted or substituted C １ -C ８ Alkyl, halogen, cyano, oxo, -O -R ５ (In the formula, R ５ is C １ -C ８ Alkyl, —CF ３ and -CHF ２ Selected from the group consisting of selected), -(CH ２ ) ｑ -OH (wherein q is 1, 2, 3, 4, 5, 6, 7, and 8) and -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ alkyl), morpholinyl, oxazolyl, -C(= O)-R ８ (In the formula, R ８ is -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ a alkyl) and C １ -C ４ alkyl) , -S(=O)-R ９ , -S(=O) ２ -R ９ , -S(=O)(=NR １０ )-R １１ and and -N=S(=O)-(R １１ ) ２ (In the formula, each R ９ are independently １ -C ４ Alkyl , -CF ３ or -NR ６ R ７ (In the formula, R ６ and R ７ is H and C １ -C ４ From alkyl is selected from the group consisting of １０ is H or C １ -C ４ alkyl, and R １１ is C １ -C ４ and substituted with one or more groups selected from the group consisting of alkyl, the law of nature; Pyridyl is unsubstituted or １ -C ８ Alkyl, oxo, C １ -C ８ Alkoxy substituted with alkyl and halogen; R １８ is a halogen].

29. The compound of claim 1, wherein the compound is a compound of formula (I-R): 【Chemistry 20】 [In the formula, R ２ is 3-(methylsulfonimidoyl)phenyl or pyridazin-4-yl; R ２２ and R ２３ are C １ -C ４ alkyl].

30. The compound of claim 1, wherein the compound is a compound of formula (IS): 【Chemistry 21】 [In the formula, R ２ is 3-(methylsulfonimidoyl)phenyl or pyridazin-4-yl; R １６ and R １８ are each halogens.

31. 2. The compound of claim 1, wherein the compound of formula (I) is 6-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (Intermediate 3); N-(1,3-benzothiazol-6-yl)-2-(4-fluoro-2-methoxy- (phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (1); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)- 5-(trifluoromethyl)pyridine-3-carboxamide (2); N-(3-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5- (Trifluoromethyl)pyridine-3-carboxamide (3); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-pyridyl)-5-(trifluoromethyl)- fluoromethyl)pyridine-3-carboxamide (4); N-(4-cyanophenyl)-2-(4-fluoro-2-methoxy-phenoxy)-5- (Trifluoromethyl)pyridine-3-carboxamide (5); 2-(4-fluoro-2-methoxy-phenoxy)-N-(4-pyridyl)-5-(trifluoromethyl)- fluoromethyl)pyridine-3-carboxamide (6); N-(6-cyano-3-pyridyl)-2-(4-fluoro-2-methoxy-phenoxy) -5-(trifluoromethyl)pyridine-3-carboxamide (7); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenoxy) (Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide (8); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-oxazol-5-yl (phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (9); N-[3-(dimethylsulfamoyl)phenyl]-2-(4-fluoro-2-methoxy) -phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (10); N-(1,3-benzothiazol-2-yl)-2-(4-fluoro-2-methoxy- (phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide (11); 2-(4-fluoro-2-methoxy-phenoxy)-N-pyrimidin-4-yl-5-( (trifluoromethyl)pyridine-3-carboxamide (12); 2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)-N- [3-(trifluoromethylsulfonyl)phenyl]pyridine-3-carboxamide (1 ３）； 2-(4-fluoro-2-methoxy-phenoxy)-N-[3-(methylsulfonimide [(2- ... ； 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-methoxy-4-pyridyl )-5-(trifluoromethyl)pyridine-3-carboxamide (15); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro- 2-Methoxy-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamine Do (16); 2-(4-fluoro-2-methoxy-phenoxy)-N-(2-methyl-4-pyridyl) -5-(trifluoromethyl)pyridine-3-carboxamide (17); 2-(4-fluoro-2-methoxy-phenoxy)-N-(6-methyl-3-pyridyl) -5-(trifluoromethyl)pyridine-3-carboxamide (18); 2-(4-fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-5-( (trifluoromethyl)pyridine-3-carboxamide (19); N-[3-[[dimethyl(oxo)]-λ ６ -sulfanylidene]amino]phenyl]- 2-(4-fluoro-2-methoxy-phenoxy)-5-(trifluoromethyl)pyridin Benzene-3-carboxamide (20); 2-(2,4-dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (21); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-morpholinophenyl)- 5-(trifluoromethyl)pyridine-3-carboxamide (22); 2-(2-chloro-4-methoxy-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (23); N-(3-methylsulfonylphenyl)-2-(2-propylphenoxy)-5-(trimethylphenyl) fluoromethyl)pyridine-3-carboxamide (24); 2-(2-methoxy-4-methyl-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (25); 2-(4-chloro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (26); 2-(2-isopropoxyphenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (27); 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-( (trifluoromethyl)nicotinamide (28); 2-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl) (Oromethyl)nicotinamide (29); 2-(2-chloro-4-methoxyphenoxy)-N-(pyridin-3-yl)-5-(trimethylsilyl) (trifluoromethyl)nicotinamide (30); 2-(3,4-difluorophenoxy)-N-(pyridin-3-yl)-5-(trifluoromethyl) (Oromethyl)nicotinamide (31); 2-(2-chloro-4-fluorophenoxy)-N-(pyridin-3-yl)-5-(trimethylsilyl) (trifluoromethyl)nicotinamide (32); 2-(2,6-dimethylphenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (33); 2-(4-fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trimethylphenyl) fluoromethyl)pyridine-3-carboxamide (34); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (trifluoromethyl)-5-(trifluoromethyl)pyridine-3-carboxamide (35); 2-(2-chloro-4-fluoro-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (36); N-(3-methylsulfonylphenyl)-2-[2-methyl-4-(trifluorometh- yl [c] phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (37) ； N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy] ci]-5-(trifluoromethyl)pyridine-3-carboxamide (38); 2-[4-(difluoromethoxy)phenoxy]-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (39); 2-[3-fluoro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (40)-5-(trifluoromethyl)pyridine-3-carboxamide ）； N-(3-methylsulfonylphenyl)-2-phenoxy-5-(trifluoromethyl) Pyridine-3-carboxamide (41); 2-(3-fluorophenoxy)-N-(3-methylsulfonylphenyl)-5-(trimethylphenyl) fluoromethyl)pyridine-3-carboxamide (42); 2-(2,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (43); 2-(4-methylphenoxy)-N-(3-methylsulfonylphenyl)-5-(trifluoromethylphenyl)- (fluoromethyl)pyridine-3-carboxamide (44); 2-(3-chloro-5-fluoro-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (45); 2-(2-isopropylphenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (46); 2-(3,4-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (47); 2-(2,4-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (48); 2-(3,5-difluorophenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (49); N-(3-methylsulfonylphenyl)-2-[4-(2,2,2-trifluoroethoxy) [c] phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (50) ； N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl] (trifluoromethylsulfanyl)phenoxy]pyridine-3-carboxamide (51); 2-[2-(dimethylamino)phenoxy]-N-(3-methylsulfonylphenyl)- 5-(trifluoromethyl)pyridine-3-carboxamide (52); N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-[2-(trifluoromethyl)phenyl] (trifluoromethyl)phenoxy]pyridine-3-carboxamide (53); 2-(2,4-dimethoxyphenoxy)-N-(3-methylsulfonylphenyl)-5- (Trifluoromethyl)pyridine-3-carboxamide (54); N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-(3,4, 5-trifluorophenoxy)pyridine-3-carboxamide (55); 2-(3,5-dichlorophenoxy)-N-(3-methylsulfonylphenyl)-5-( (trifluoromethyl)pyridine-3-carboxamide (56); N-(3-methylsulfonylphenyl)-5-(trifluoromethyl)-2-[[6-( trifluoromethyl)-3-pyridyl]oxy]pyridine-3-carboxamide (57) ； 2-(1,3-benzothiazol-4-yloxy)-N-(3-methylsulfonylphenyl) (Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide (58); 2-[4-(difluoromethoxy)phenoxy]-N-[3-(methylsulfonimide) [phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (59); 2-(2-chloro-4-fluoro-phenoxy)-N-[3-(methylsulfonimide) [phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (60); 2-(2-chloro-4-methoxy-phenoxy)-N-[3-(methylsulfonimide) [phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (61); 2-(2-chlorophenoxy)-N-[3-(methylsulfonimidoyl)phenyl]- 5-(trifluoromethyl)pyridine-3-carboxamide (62); 2-(2,4-dichlorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl) Methyl)pyridine-3-carboxamide (63); 2-[4-(difluoromethoxy)phenoxy]-N-pyridazin-4-yl-5-(trifluoromethyl)- (trifluoromethyl)pyridine-3-carboxamide (64); 2-(2-chloro-4-methoxy-phenoxy)-N-pyridazin-4-yl-5-(trimethylsilyl) (trifluoromethyl)pyridine-3-carboxamide (65); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (trifluoromethyl)-6-(trifluoromethyl)pyridine-3-carboxamide (66); 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (trifluoromethyl)-6-(trifluoromethyl)pyridine-3-carboxamide (67); 4-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfinylphenoxy) (68)-6-(trifluoromethyl)pyridine-3-carboxamide; 4-(4-fluoro-2-methoxy-phenoxy)-N-(2-fluoro-5-methylsulfonyl) (6-(trifluoromethyl)pyridine-3-carboxamide) ９）； N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-4-(4-fluoro- 2-Methoxy-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamine Do (70); 4-(4-fluoro-2-methoxy-phenoxy)-N-pyridazin-4-yl-6-( (trifluoromethyl)pyridine-3-carboxamide (71); 4-(4-fluoro-2-methoxy-phenoxy)-N-(4-pyridyl)-6-(trifluoromethyl)- fluoromethyl)pyridine-3-carboxamide (72); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[2-(dimethyl Amino)-4-pyridyl]-6-(trifluoromethyl)pyridine-3-carboxamide （７３）； 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (phenylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (74) ； 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (phenylphenyl)-6-(trifluoromethyl)pyridine-3-carboxamide (75 ）； 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethyl sulfamoyl)phenyl]-6-(trifluoromethyl)pyridine-3-carboxamine Do (76); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro- 5-Methylsulfonyl-phenyl)-6-(trifluoromethyl)pyridine-3-carbo oxamide (77); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-pyridyl) -6-(trifluoromethyl)pyridine-3-carboxamide (78); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(4-pyridyl) -6-(trifluoromethyl)pyridine-3-carboxamide (79); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(methylsulfonyl) [6-(trifluoromethyl)pyridine-3-carboxamide] Mido (80); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S- Dimethylsulfonimidoyl)phenyl]-6-(trifluoromethyl)pyridine-3- Carboxamide (82); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-oxidopyridine) Lysin-1-ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxylate Samid (83); 4-(4-fluoro-2-methoxy-phenoxy)-N-(1-oxidopyridine-1- (ium-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (84 ）； 4-(4-fluoro-2-methyl-phenoxy)-N-(1-oxidopyridin-1-yl) (Um-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (85) ； 4-[4-(difluoromethoxy)phenoxy]-N-(1-oxidopyridin-1-yl) (Um-3-yl)-6-(trifluoromethyl)pyridine-3-carboxamide (86) ； N-(1-oxidopyridin-1-ium-3-yl)-4-[4-(trifluoromethyl) [0047] -6-(trifluoromethyl)pyridine-3-carboxamide (87 ）； 4-(2,4-dimethoxyphenoxy)-N-(1-oxidepyridin-1-ium-3 -yl)-6-(trifluoromethyl)pyridine-3-carboxamide (88); 4-(2,4-difluorophenoxy)-N-(1-oxidepyridin-1-ium-3 -yl)-6-(trifluoromethyl)pyridine-3-carboxamide (89); 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinic acid (mido)pyridine-1-oxide (90); N-[3-(methylsulfonimidoyl)phenyl]-4-[4-(trifluoromethacrylamide) [c]phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide (91) ； N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-4-[4-(trifluoromethyl)phenyl] (trifluoromethoxy)phenoxy]-6-(trifluoromethyl)pyridine-3-carboxamide Do (92); 4-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimide) [phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (93); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-4-(4-fluoro- 2-methyl-phenoxy)-6-(trifluoromethyl)pyridine-3-carboxamide （９４）； 4-(4-fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl)- (trifluoromethyl)pyridine-3-carboxamide (95); N-pyridazin-4-yl-4-[4-(trifluoromethoxy)phenoxy]-6-( (trifluoromethyl)pyridine-3-carboxamide (96); 4-[4-(difluoromethoxy)phenoxy]-N-pyridazin-4-yl-6-(trifluoromethyl)- (trifluoromethyl)pyridine-3-carboxamide (97); 4-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazine-4- yl-6-(trifluoromethyl)pyridine-3-carboxamide (98); 4-(2,4-dimethoxyphenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl) (trimethyl)pyridine-3-carboxamide (99); 4-(2,4-difluorophenoxy)-N-pyridazin-4-yl-6-(trifluoromethyl) (trimethyl)pyridine-3-carboxamide (100); 4-[4-(difluoromethoxy)phenoxy]-N-[3-(methylsulfonimide) [phenyl]-6-(trifluoromethyl)pyridine-3-carboxamide (101) ； 4-(2,4-dimethoxyphenoxy)-N-[3-(methylsulfonimidoyl)phenoxy] Nyl]-6-(trifluoromethyl)pyridine-3-carboxamide (102); 4-(2,4-difluorophenoxy)-N-[3-(methylsulfonimidoyl)phenoxy] Nyl]-6-(trifluoromethyl)pyridine-3-carboxamide (103); 2-(4-(difluoromethoxy)phenoxy)-N-(pyridin-3-yl)-5-( (trifluoromethyl)nicotinamide (104); N-(pyridin-3-yl)-4-(4-(trifluoromethoxy)phenoxy)-6- (Trifluoromethyl)nicotinamide (105) 4-(2-chloro-4-(trifluoromethoxy)phenoxy)-N-(pyridine-3- (yl)-6-(trifluoromethyl)nicotinamide (106); 4-(2,4-dimethoxyphenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl) (Oromethyl)nicotinamide (107); 4-(2,4-difluorophenoxy)-N-(pyridin-3-yl)-6-(trifluoromethyl) (Oromethyl)nicotinamide (108); 2-(4-fluoro-2-methyl-phenoxy)-N-(2-methoxy-4-pyridyl) -5-(trifluoromethyl)pyridine-3-carboxamide (109); 2-(4-fluoro-2-methyl-phenoxy)-N-(2-oxo-1H-pyridine- 4-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (110); 5-Bromo-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (111); 5-cyclopropyl-2-(4-fluoro-2-methoxyphenoxy)-N-(3-methyl- (Cysulfonylphenyl)pyridine-3-carboxamide (112); 2-(4-fluoro-2-methyl-phenoxy)-N-(3-methylsulfonylphenyl )-5-(trifluoromethyl)pyridine-3-carboxamide (113); N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-(4-fluoro- 2-methyl-phenoxy)-5-(trifluoromethyl)pyridine-3-carboxamide （１１４）； 2-(4-fluoro-2-methyl-phenoxy)-N-[3-(methylsulfonimide) [phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (115) ； 2-(4-fluoro-2-methyl-phenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl)- (trifluoromethyl)pyridine-3-carboxamide (116); 2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (117); 2-(4-fluoro-2-methoxy-phenoxy)-5,6-dimethyl-N-(3-methyl (phenylsulfonylphenyl)pyridine-3-carboxamide (118); 5-chloro-2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonyl) (phenylphenyl)pyridine-3-carboxamide (119); 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-methylsulfonylphenyl) (1)-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxamide ２０）； N-(3-methylsulfinylphenyl)-2-[4-(trifluoromethoxy)pheno] oxy]-5-(trifluoromethyl)pyridine-3-carboxamide (121); N-(3-sulfamoylphenyl)-2-[4-(trifluoromethoxy)phenoxy] ]-5-(trifluoromethyl)pyridine-3-carboxamide (122); N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethacrylamide) 1) phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (123 ）； N-[3-(N,S-dimethylsulfonimidoyl)phenyl]-2-[4-(trifluoromethyl)phenyl] [0049]-5-(trifluoromethyl)pyridine-3-carboxamide Do (124); N-(3-ethylsulfonylphenyl)-2-[4-(trifluoromethoxy)phenoxy] ci]-5-(trifluoromethyl)pyridine-3-carboxamide (125); N-(3-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)- fluoromethyl)pyridine-3-carboxamide (126); N-(4-pyridyl)-2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)- fluoromethyl)pyridine-3-carboxamide (127); N-pyridazin-4-yl-2-[4-(trifluoromethoxy)phenoxy]-5-( (trifluoromethyl)pyridine-3-carboxamide (128); N-[3-[[dimethyl(oxo)]-λ ６ -sulfanylidene]amino]phenyl]- 2-[4-(trifluoromethoxy)phenoxy]-5-(trifluoromethyl)pyridin thiazol-3-carboxamide (129); N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethacrylamide) (c) phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, enanthate Thiomer A (130); N-[3-(methylsulfonimidoyl)phenyl]-2-[4-(trifluoromethacrylamide) (c) phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide, enanthate Thiomer B (131); N-(1-oxidopyridin-1-ium-3-yl)-2-[4-(trifluoromethyl) [0023] -5-(trifluoromethyl)pyridine-3-carboxamide (13 ２）； 2-(4-fluoro-2-methyl-phenoxy)-N-(1-oxidopyridin-1-yl) um-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (133 ）； 2-(4-fluoro-2-methoxy-phenoxy)-N-(1-oxidopyridine-1- (ium-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (13 ４）； 2-(2,4-difluorophenoxy)-N-(1-oxidepyridin-1-ium-3 -yl)-5-(trifluoromethyl)pyridine-3-carboxamide (135); 3-(2-(4-(difluoromethoxy)phenoxy)-5-(trifluoromethyl)di Cotinamide)pyridine 1-oxide (136); 3-(2-(2,4-dimethoxy)phenoxy)-5-(trifluoromethyl)nicotine Amido)pyridine 1-oxide (137); 3-(2-(2-chloro-4-methoxyphenoxy)-5-(trifluoromethyl)nicotinamide tinamide)pyridine 1-oxide (138); 3-(2-(3,4-difluorophenoxy)-5-(trifluoromethyl)nicotinic acid (mido)pyridine 1-oxide (139); 2-(2-chloro-4-fluoro-phenoxy)-N-(1-oxidopyridin-1-yl) um-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (140 ）； N-(1-oxidopyridin-1-ium-4-yl)-2-[4-(trifluoromethyl) [oxy)phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (14 １）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-methylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (142 ）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-ethylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (143 ）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(N,S- Dimethylsulfonimidoyl)phenyl]-5-(trifluoromethyl)pyridine-3- Carboxamide (144); 4-pyridyl 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-5-( (trifluoromethyl)pyridine-3-carboxylate (145); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-cyanophenoxy) (Nyl)-5-(trifluoromethyl)pyridine-3-carboxamide (146); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methylpyrrolidone) (4-isopropyl-5-(trifluoromethyl)pyridine-3-carboxamide (14 ７）； N-(3-carbamoylphenyl)-2-[2-chloro-4-(trifluoromethoxy) phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (148); N-(3-acetylphenyl)-2-[2-chloro-4-(trifluoromethoxy)phenyl] [noxy]-5-(trifluoromethyl)pyridine-3-carboxamide (149); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-2 -oxo-4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide （１５０）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethyl [carbamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide （１５１）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (152 ）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(4-methylsulfonyl) (phenylphenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (153 ）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(dimethyl sulfamoyl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamine Do (154); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3,4-difluoromethyl) (fluorophenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (155) ； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(6-methoxy- 3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (156) ； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-pyrimidine-5- yl-5-(trifluoromethyl)pyridine-3-carboxamide (157); N-(2-chloro-4-pyridyl)-2-[2-chloro-4-(trifluoromethoxy) phenoxy]-5-(trifluoromethyl)pyridine-3-carboxamide (158); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(6-fluoro- 3-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (159) ； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-[3-(hydroxy [Dimethyl]phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (1 ６０）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-pyridazine-4- yl-5-(trifluoromethyl)pyridine-3-carboxamide (161); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro- 5-Methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carbo oxamide (162); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(3-fluorophenyl) (phenyl)-5-(trifluoromethyl)pyridine-3-carboxamide (163); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-4 -pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (164); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-fluoro- 4-pyridyl)-5-(trifluoromethyl)pyridine-3-carboxamide (165) ； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(thiadiazole -5-yl)-5-(trifluoromethyl)pyridine-3-carboxamide (166); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methylpyrrolidone (16)-5-(trifluoromethyl)pyridine-3-carboxamide ７）； 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-5 -methylsulfonyl-phenyl)-5-(trifluoromethyl)pyridine-3-carboxylate Samid (168); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(2-methyl-1 ,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide Voxamide (169); 2-[2-chloro-4-(trifluoromethoxy)phenoxy]-N-(1-methyl-1 ,2,4-triazol-3-yl)-5-(trifluoromethyl)pyridine-3-carboxamide Voxamide (170); 2-(2,4-dimethoxyphenoxy)-N-[3-(N,S-dimethylsulfonimide] [0033] 5-(trifluoromethyl)pyridine-3-carboxamide (171 ）； 2-(2,4-dimethoxyphenoxy)-N-[3(methylsulfonimidoyl)phenyl] [yl]-5-(trifluoromethyl)pyridine-3-carboxamide (172); 2-(2,4-dimethoxyphenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl) (trimethyl)pyridine-3-carboxamide (173); 2-(2,4-difluorophenoxy)-N-[3-(methylsulfonimidoyl)phenoxy] Nyl]-5-(trifluoromethyl)pyridine-3-carboxamide (174); 2-(2,4-difluorophenoxy)-N-[3-(N,S-dimethylsulfonimide] (yl)phenyl]-5-(trifluoromethyl)pyridine-3-carboxamide (175 ）； 2-(2,4-difluorophenoxy)-N-pyridazin-4-yl-5-(trifluoromethyl) (trimethyl)pyridine-3-carboxamide (176); 5-cyano-2-(4-fluoro-2-methoxy-phenoxy)-6-methyl-N-(3 -methylsulfonylphenyl)pyridine-3-carboxamide (177); 5-fluoro-2-(4-fluoro-2-methoxy-phenoxy)-6-methoxy-N- (3-methylsulfonylphenyl)pyridine-3-carboxamide (178); 5-(difluoromethoxy)-2-(4-fluoro-2-methoxy-phenoxy)-N- (3-methylsulfonylphenyl)pyridine-3-carboxamide (179); N-(3-methylsulfonylphenyl)-5-nitro-2-[4-(trifluoromethylphenyl) xi) phenoxy]pyridine-3-carboxamide (180); and 5-chloro-N-(3-methylsulfonylphenyl)-2-[4-(trifluoromethacrylamide) C) Phenoxy]pyridine-3-carboxamide (181) A compound selected from the group consisting of:

32. Na ｖ 1.8 A method for modulating sodium ion channels in a subject in need thereof administering to a subject a compound according to any one of claims 1 to 31 in an amount effective to modulate said subject; The method of claim 1, wherein the

33. Na ｖ 1. A method of inhibiting HIV-1, HIV-2, or HIV-3, comprising administering to a subject in need thereof a therapeutically effective amount of HIV-1, HIV-2, or HIV-3-mediated ischemic heart failure.

32. A method comprising administering an inhibitory effective amount of a compound according to any one of claims 1 to 31 to Law.

34. Na ｖ 1.8 and to treat symptoms of pathologies, diseases or disorders associated with increased activity or expression 20. A method for the treatment and / or amelioration of a condition that is therapeutic for said subject, comprising administering to a subject in need thereof 30. The method of claim 1, wherein the method comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 29 to treat said disease.

2. A method for treating and / or alleviating the symptoms of a condition, disease or disorder.

35. Na ｖ 1. The pathological conditions, diseases or disorders associated with increased activity or expression of 1.8 include pain, respiratory a patient with a medical condition selected from the group consisting of an organ disorder, a neurological disorder and a psychiatric disorder, and a combination thereof; The method of claim 34.

36. the pain is neuropathic pain, inflammatory pain, visceral pain, cancer pain, or chemotherapy-induced pain; Traumatic pain, surgical pain, postoperative pain, childbirth pain, labor pain, neuropathic bladder, ulcerative colitis, chronic pain. pain, persistent pain, peripheral pain, central pain, chronic headache, migraine, sinus headache, urgent pain a pain-relieving agent selected from the group consisting of tension headache, phantom limb pain, toothache, peripheral nerve injury, and combinations thereof; 36. The method of claim 35,

37. The disease or condition is HIV treatment-induced neuropathy, trigeminal neuralgia, postherpetic neuropathy, Pain, eudynia, heat hypersensitivity, tosarcoidosis dosis), irritable bowel syndrome, Crohn's disease, multiple sclerosis (MS), amyotrophic lateral sclerosis ALS, diabetic neuropathy, peripheral neuropathy, arthritis, rheumatoid arthritis , osteoarthritis, atherosclerosis, paroxysmal dystonia, myasthenic syndrome, myotonia , malignant hyperthermia, cystic fibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, Bipolar depression, anxiety disorders, schizophrenia, sodium channel toxin-related disorders, familial erythromelalgia disease, primary erythromelalgia, familial rectalgia, cancer, epilepsy, partial and generalized tonic seizures, Restless legs syndrome, cardiac arrhythmia, fibromyalgia, ischemia caused by stroke or neurotrauma Neuroprotection under conditions of tachyarrhythmia, atrial fibrillation, ventricular fibrillation, and Pitt-Hopkins syndrome 36. The method of claim 35, wherein the PTHS is selected from the group consisting of:

38. 35. The method of claim 34, further comprising administering to the subject one or more additional therapeutic agents. How to post.

39. the one or more additional therapeutic agents are acetaminophen, one or more NSAIDs, 39. The method of claim 38, wherein the analgesic is selected from the group consisting of opioid analgesics and combinations thereof. How to do it.

40. Na ｖ The treatment of conditions, diseases or disorders associated with increased activity or expression of 1.8 is provided herein. Use of a compound of formula (I) in the manufacture of a medicament for administration to a subject suffering from a disorder 。

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